Sulfonamide compound or salt thereof

ABSTRACT

A compound represented by Formula (I) [wherein, X1 represents an oxygen atom or the like; X2 represents an oxygen atom; X3 represents —NH—; X4 represents a hydrogen atom or the like; R1 represents —C(R11)(R12)— or the like; R11 and R12 are the same or different and each represents a hydrogen atom or the like; R2 represents an optionally substituted C6-C14 aromatic hydrocarbon group or the like; R3 represents an optionally substituted C6-C14 aromatic hydrocarbon group or the like; R4 represents a hydrogen atom or the like] or a salt thereof.

TECHNICAL FIELD

The present invention relates to a novel sulfonamide compound having a ribonucleotide reductase inhibitory activity or a salt thereof, and a pharmaceutical composition containing the same as an active ingredient.

BACKGROUND

Ribonucleotide reductase (hereinafter also referred to as RNR) is composed of a hetero-oligomer of a large subunit M1 and a small subunit M2, and expression of both is required for enzyme activity. RNR recognizes ribonucleoside 5′-diphosphate (hereinafter also referred to as NDP) as a substrate and catalyzes a reduction reaction to 2′-deoxyribonucleoside 5′-diphosphate (hereinafter also referred to as dNDP). Since RNR is a rate-limiting enzyme in the de novo dNTP synthesis pathway, RNR plays an essential role in DNA synthesis and repair (Non-Patent Document 1).

The enzymatic activity of RNR is closely related to cell proliferation, and there is a report that the enzymatic activity is particularly high in cancer (Non-Patent Document 2). Indeed, in various types of solid tumors and blood cancers, numerous correlations have been reported with overexpression of M2, a subunit of RNR, and their prognosis (Non-Patent Documents 3 and 4). In addition, cell growth inhibition by inhibiting RNR and anti-tumor effect in vivo have been reported in cell lines derived from several cancer types and in nonclinical models (Non-Patent Documents 5 and 6), thus it is strongly suggested that RNR is one of important target molecules for cancer treatment.

Conventionally, hydroxyurea (hereinafter also referred to as HU) and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (hereinafter also referred to as 3-AP) are known as compounds having an RNR inhibitory activity. These compounds differ in structure from the sulfonamide compounds of the present invention. Although HU has been used clinically for over 30 years, its RNR inhibitory activity is very weak and its effect is limited (Non-Patent Document 7). In addition, tolerance to the use of HU is also considered a problem (Non-Patent Document 8). Meanwhile, 3-AP has a structure having the capability to chelate to metal ions, and it has been known that 3-AP chelates mainly to iron ions, thereby inhibiting RNR (Non-Patent Document 9). However, 3-AP has been suggested as having an off-target effect to various other iron-ion-requiring proteins, and it has been known that side effects such as hypoxia, dyspnea, methemoglobinemia and the like are caused in clinical cases (Non-Patent Document 10).

Therefore, it has been strongly desired to develop an RNR inhibitor which has a better RNR inhibitory activity and a structure which does not chelate with metal ions and is useful for diseases associated with RNR, such as tumors.

Meanwhile, as a compound having a sulfonamide structure, Non-Patent Document 11 discloses a compound (4a-e) having the following formula:

(wherein, R represents CH₂Ph, and R′ represents Me). However, the compound (4a-e) is a production intermediate for obtaining the 5-benzylthio-1,3,4-oxadiazole derivatives as an objective compound having an anti-HIV activity. Non-Patent Document 11 does not disclose a physiological activity of the compound (4a-e), and does not suggest an RNR inhibition activity and antitumor effects of the compound (4a-e).

PRIOR ART DOCUMENT Non-Patent Document

-   [Non-Patent Document 1] Annu. Rev. Biochem. 67, 71-98. (1998) -   [Non-Patent Document 2] J. Biol. Chem. 245, 5228-5233. (1970) -   [Non-Patent Document 3] Nat. Commun. 5, 3128 doi: 10.1038/ncomms     4128 (2014) -   [Non-Patent Document 4] Clin. Sci. 124, 567-578. (2013) -   [Non-Patent Document 5] Expert. Opin. Ther. Targets 17, 1423-1437     (2013) -   [Non-Patent Document 6] Biochem. Pharmacol. 59, 983-991 (2000) -   [Non-Patent Document 7] Biochem. Pharmacol. 78, 1178-11 85 (2009) -   [Non-Patent Document 8] Cancer Res. 54, 3686-3691 (1994) -   [Non-Patent Document 9] Pharmacol. Rev. 57, 547-583 (2005) -   [Non-Patent Document 10] Future Oncol. 8, 145-150 (2012) -   [Non-Patent Document 11] J. Enzym. Inhib. Med. Chem. 26, 5, 668-680     (2011)

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a novel compound which selectively and strongly inhibits RNR and is useful as an antitumor agent and a therapeutic agent for other diseases involving RNR.

Means to be Solved by the Invention

As a result of extensive studies to solve the above-mentioned problems, the inventors of the present invention have found that a group of compounds having a sulfonamide structure represented by the following formula (I) has excellent RNR inhibitory activity, and is useful as an antitumor agent etc., and completed the present invention.

The present invention provides the following: [1] to [33].

[1]

A compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, or a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents,

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)]

or a salt thereof.

[2]

The compound or a salt thereof according to [1], wherein in formula (I):

R¹¹ represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group;

R¹² represents a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group; or

R¹¹ and R¹² may be taken together with carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms.

[3]

The compound or a salt thereof according to [1] or [2], wherein in formula (I), X¹ represents an oxygen atom.

[4]

The compound or a salt thereof according to any one of [1]-[3], wherein in formula (I), X² represents an oxygen atom.

[5]

The compound or a salt thereof according to any one of [1]-[4], wherein in formula (I), X³ represents —NH—.

[6]

The compound or a salt thereof according to any one of [1]-[5], wherein in formula (I), X⁴ represents a hydrogen atom.

[7]

The compound or a salt thereof according to any one of [1]-[6], wherein in formula (I), R¹ represents —C(R¹¹)(R¹²)— (in which R¹¹ represents a C1-C6 alkyl group, and R¹² represents a hydrogen atom).

[8]

The compound or a salt thereof according to any one of [1]-[7], wherein in formula (I):

R² represents a C6-C14 aromatic hydrocarbon group or a 9-10 membered fully unsaturated heterocyclic group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may be substituted with Rz;

R²¹ represents: a halogen atom; an amino carbonyl group; a cyano group; a C1-C6 alkyl group optionally substituted with Rx; a C3-C6 cycloalkyl group optionally substituted with Rx; a C2-C6 alkynyl group optionally substituted with Rx; a C6-C14 aromatic hydrocarbon group optionally substituted with Ry; or a 5-10 membered unsaturated heterocyclic group optionally substituted with Rz;

Rx represents a halogen atom or a C6-C14 aromatic hydrocarbon group;

Ry represents a halogen atom or a C1-C6 alkoxy group;

Rz represents a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, or a nitrogen-containing saturated heterocyclic carbonyl group.

[9]

The compound or a salt thereof according to any one of [1]-[8], wherein in formula (I):

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group, wherein R³ may be substituted with R³¹, and when R³ has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituent may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may be substituted with Rc;

R³¹ represents: a halogen atom; a cyano group; a nitro group; a carboxyl group; a thioamide group; a C1-C6 alkyl group optionally substituted with Ra; an amino group optionally substituted with Ra; a C3-C6 cycloalkyl group optionally substituted with Rb; a C1-C6 alkoxy group optionally substituted with Rb; a C2-C7 alkoxycarbonyl group; a C1-C14 acyl group optionally substituted with Rb; a C6-C14 aromatic hydrocarbon group optionally substituted with Rb; a 5-10 membered unsaturated heterocyclic group optionally substituted with Rc; an amino carbonyl group optionally substituted with Rd and Re; or —S(═O)₂Rf;

Ra represents a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group;

Rb represents a halogen atom, an amino group, or a C1-C6 alkoxy group;

Rc represents: a halogen atom; a hydroxy group; an amino group; an oxo group; a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl groups; a C1-C14 acyl groups; a C1-C14 acylamino group; a C1-C14 acyloxy group; or a C7-C13 aralkyloxy group;

Rd and Re are the same or different and represent: a hydrogen atom; a hydroxy group; a C7-C13 aralkyloxy group; or C1-C6 alkyl group optionally substituted with a hydroxyl group; alternatively taken together with nitrogen atom which is adjacent to Rd and Re to form a saturated or unsaturated 4-10 membered heterocyclic ring group optionally substituted with an amino group, a spiro heterocyclic ring group, or a bridged heterocyclic ring group; and

Rf represents an amino group, a C1-C6 alkyl group, or a 4-10 membered saturated heterocyclic group.

[10]

The compound or a salt thereof according to any one of [1]-[9], wherein in formula (I):

R² represents a C6-C14 aromatic hydrocarbon group or a bicyclic 9-10 membered fully unsaturated heterocyclic ring group having 1-3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 4-8 carbon atoms (optionally substituted with a C1-C6 alkyl group) or a saturated or partially unsaturated monocyclic 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a C1-C6 alkyl group);

R²¹ represents a halogen atom, an amino carbonyl group, a cyano group, a C1-C6 alkyl group (optionally substituted with halogen atoms), a C3-C6 cycloalkyl group, a C2-C6 alkynyl group (optionally substituted with C6-C14 aromatic hydrocarbons groups), a C6-C14 aromatic hydrocarbon group (optionally substituted with group selected from a halogen atom and a C1-C6 alkoxy group), or an unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1-3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, and nitrogen-containing saturated heterocyclic carbonyl group).

[11]

The compound or a salt thereof according to any one of [1]-[10], wherein in formula (I):

R² represents a C6-C14 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 4-8 carbon atoms (optionally substituted with a C1-C6 alkyl group);

R²¹ represents a halogen atom, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkoxy group), or an unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1-3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group).

[12]

The compound or a salt thereof according to any one of [1]-[11], wherein in formula (I):

R² represents a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 5 or 6 carbon atoms (optionally substituted with a C1-C6 alkyl group);

R²¹ represents a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6 membered unsaturated heterocyclic group having 1-3 nitrogen atom(s) (optionally substituted with a C1-C6 alkyl group).

[13]

The compound or a salt thereof according to any one of [1]-[12], wherein in formula (I):

R³ represents a C6-C14 aromatic hydrocarbon group, or a monocyclic or bicyclic 5-10 membered fully unsaturated heterocyclic group having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ may be substituted with R³¹, and when R³ has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 4-8 carbon atoms (optionally substituted with a group selected from the group consisting of a halogen atom; a hydroxy group; an amino group; an oxo group; a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; a C1-C14 acyloxy group; and a C7-C13 aralkyloxy group), or a saturated or partially unsaturated monocyclic 4-8 membered heterocyclic ring having 1-4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; a C1-C14 acyloxy group and a C7-C13 aralkyloxy group);

R³¹ represents a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, C1-C14 acyloxy group, a C2-C6 alkynyl group, and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group (optionally substituted with a C1-C14 acyl group), a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), a C6-C14 aromatic hydrocarbon group (optionally substituted with a group selected from the group consisting of a halogen atom, an amino group and a C1-C6 alkoxy group), a monocyclic or bicyclic 5-10 membered unsaturated heterocyclic group having 1-4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted a group selected from with the group consisting of a halogen atom, an oxo group and a C1-C6 alkyl group), an amino carbonyl group optionally substituted with Rd and Re (wherein Rd and Re are the same or different, and present a hydrogen atom, a hydroxy group, a C7-C13 aralkyloxy group, or a C1-C6 alkyl group optionally substituted with a hydroxy group, alternatively taken together with the adjacent nitrogen atom to form: a saturated or unsaturated monocyclic or bicyclic 4-10 membered heterocyclic group, optionally substituted with an amino group, having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom; a spiro heterocyclic group; or a bridged heterocyclic group), or —S(═O)₂Rf (wherein Rf represents an amino group, a C1-C6 alkyl group, or a 4-10 membered saturated heterocyclic group).

[14]

The compound or a salt thereof according to any one of [1]-[13], wherein in formula (I):

R³ represents a C6-C10 aromatic hydrocarbon group or a fully unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ may be substituted with R³¹, when R³ has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, R³ may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic hydrocarbon having 4-8 carbon atoms (optionally substituted with groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group (which is optionally substituted with a hydroxy group), a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a saturated or partially unsaturated monocyclic 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of: a halogen atom; a hydroxy group; an amino group; an oxo group; and a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; and a C1-C14 acyloxy group);

R³¹ represents a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group, a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), a C6-C10 aromatic hydrocarbon group (optionally substituted with a halogen atom), an unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group consisting of a C1-C6 alkyl group and an oxo group), a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyamino carbonyl group, (C7-C13 aralkyloxy)oxyaminocarbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl group.

[15]

The compound or a salt thereof according to any one of [1]-[14], wherein in formula (I):

R³ represents a C6-C10 aromatic hydrocarbon group (wherein the C6-C10 aromatic hydrocarbon group may be substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic 4-6 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms (optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group; a C1-C14 acyl amino group and a C1-C14 acyloxy group)), alternatively presents a fully unsaturated monocyclic 5 or 6 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of: a halogen atom; a C1-C6 alkyl group optionally substituted with a hydroxy group; a C1-C6 alkoxy group; a C2-C7 alkoxycarbonyl group; a —CONH₂ group; a (mono- or di-C1-C6 alkyl)aminocarbonyl group; a pyrrolidin-1-ylcarbonyl group; a morpholin-4-ylcarbonyl group; a 2-oxa-7-azaspiro[3.5]nonanyl group; a 3-oxa-8-azabicyclo[3.2.1]octanyl group; and an 8-oxa-3-azabicyclo[3.2.1]octanyl group),

R³¹ represents a halogen atom, an amino group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), an unsaturated monocyclic 5 or 6 membered heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono or di-C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino carbonyl group.

[16]

The compound or a salt thereof according to any one of [1]-[15], wherein in formula (I):

X¹ represents an oxygen atom,

X² represents an oxygen atom,

X³ represents —NH—,

X⁴ represents a hydrogen atom,

R¹ represents —C(R¹¹)(R¹²)— (wherein R¹¹ represents a C1-C6 alkyl group, and R¹² represents a hydrogen atom), and

R² represents a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 5 or 6 carbon atoms (optionally substituted with a C1-C6 alkyl group); and

R²¹ represents a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6 membered unsaturated heterocyclic group having 1-3 nitrogen atom(s) (optionally substituted with a C1-C6 alkyl group);

R³ represents a C6-C10 aromatic hydrocarbon group (wherein the C6-C10 aromatic hydrocarbon group may be substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substitutes may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic 4-6 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acyl amino group, and a C1-C14 acyloxy group)), alternatively presents a fully unsaturated monocyclic 5 or 6 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxy group, a C1-C6 alkoxy group, a C2-C7 alkoxycarbonyl group, a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group, a 3-oxa-8-azabicyclo[3.2.1]octanyl group and an 8-oxa-3-azabicyclo[3.2.1]octanyl group),

R³¹ represents a halogen atom, an amino group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a monocyclic 5 or 6 membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono or di-C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino carbonyl group.

R⁴ represents a hydrogen atom.

[17]

The compound or a salt thereof according to any one of [1]-[16], wherein in formula (I):

X¹ represents an oxygen atom,

X² represents an oxygen atom,

X³ represents —NH—,

X⁴ represents a hydrogen atom,

R¹ represents —C(R¹¹)(R¹²)— (wherein R¹¹ represents a methyl group, and R¹² represents a hydrogen atom), and

R² represents a phenyl group, or a naphthyl group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached, to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 5 or 6 carbon atoms (optionally substituted with a C1-C6 alkyl group); and

R²¹ represents a halogen atom or a C1-C6 alkyl group;

R³ represents a phenyl group (wherein the phenyl group may be substituted with R³¹, and when a phenyl group has two substituents on the carbon atoms which are adjacent each other on a benzene ring, the substitutes may be fused together with carbon atoms to which the substituents are attached to form a saturated or partially unsaturated monocyclic 6 membered heterocyclic ring having 1 or 2 oxygen atom(s) (optionally substituted with a group selected from the group consisting of a hydroxy group and a C1-C6 alkyl group)), or a pyridyl group (optionally substituted with a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, or a pyrrolidin-1-ylcarbonyl group);

R³¹ represents a halogen atom, an amino group, a C1-C6 alkyl group or a —CONH₂ group;

R⁴ represent a hydrogen atom.

[18]

The compound or a salt thereof according to any one of claims 1-17, wherein the compound is selected from the following compounds (1)-(19):

-   (1)     5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (2)     5-chloro-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (3)     5-bromo-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (4)     5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide -   (5)     5-chloro-2-(N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (6)     5-chloro-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (7)     5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (8)     5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (9)     2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chloro-benzamide; -   (10)     5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(pyrrolidine-1-carbonyl)pyridine-2-sulfonamide; -   (11)     5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide; -   (12) 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methyl     phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-chroman-8-sulfonamide; -   (13)     N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methylchroman-8-sulfonamide; -   (14)     5-Chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)     propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide; -   (15)     5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4     oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide; -   (16)     3-Chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N,N-dimethylpicolinamide; -   (17)     4-Amino-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide; -   (18)     4-Amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide;     or -   (19)     5-chloro-2-((1S,2R)-methyl-d3-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide.     [19]

A ribonucleotide reductase inhibitor comprising the compound or a salt thereof according to any one of [1]-[16] as an active ingredient.

[20]

A medicament comprising the compound or a salt thereof according to any one of [1]-[18].

[21]

A pharmaceutical composition comprising the compound or a salt thereof according to any one of [1]-[18] and a pharmaceutically acceptable carrier.

[22]

An anti-tumor agent comprising the compound or a salt thereof according to any one of [1]-[18] as an active ingredient.

[23]

An anti-tumor agent for oral administration comprising the compound or a salt thereof according to any one of [1]-[18] as an active ingredient.

[24]

Use of the compound or a salt thereof according to any one of [1]-[18] for manufacturing a ribonucleotide reductase inhibitor.

[25]

Use of the compound or a salt thereof according to any one of [1]-[18] for manufacturing a pharmaceutical composition.

[26]

Use of the compound or a salt thereof according to any one of [1]-[18] for manufacturing an anti-tumor agent.

[27]

Use of the compound or a salt thereof according to any one of [1]-[18] for manufacturing an antitumor agent for oral administration.

[28]

The compound or a salt thereof according to any one of [1]-[18] for use for inhibiting ribonucleotide reductase.

[29]

The compound or a salt thereof according to any one of [1]-[18] for use as a medicament.

[30]

The compound or a salt thereof according to any one of [1]-[18] for use for preventing and/or treating tumors.

[31]

The compound or a salt thereof according to any one of [1]-[18] for use for preventing and/or treating tumors by oral administration.

[32]

A method of inhibiting ribonucleotide reductase comprising administering an effective amount of the compound or a salt thereof according to any one of [1]-[18] to a subject in need thereof.

[33]

A method of preventing and/or treating tumors comprising administering an effective amount of the compound or a salt thereof according to any one of [1]-[18] to a subject in need thereof.

Effect of the Invention

According to the present invention, the novel sulfonamide compounds represented by the above formula (I) or salts thereof useful as RNR inhibitors are provided.

The compounds of the present invention or a salt thereof have an excellent RNR-inhibiting activity, and show a growth inhibitory effect for cancer cell lines. Accordingly, the compounds of the present invention or a salt thereof are useful as an anti-tumor agent and a therapeutic agent for other diseases where RNR are involved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 It is a diagram illustrating daily variation of relative tumor volume (hereinafter also referred to as “RTV”) with the compound according to the present invention.

FIG. 2 It is a diagram showing daily variation of RTV with the compound according to the present invention.

FIG. 3 It is a diagram showing daily variation of RTV with the compound according to the present invention.

FIG. 4 It is a diagram showing daily variation of RTV with the compound according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention represented by formula (I) are compounds having a sulfonamide structure, and are novel compounds which are not described in the prior art literature described hereinafter.

“CA-CB” as used herein refers to a group having a carbon number of A-B in the present specification. For example, “C1-C6 alkyl group” represents an alkyl group having 1 to 6 carbon atoms. The term “A-B members” indicates that the number of atoms constituting the ring (ring members) is A-B. For example, “5-10 membered unsaturated heterocyclic group” means an unsaturated heterocyclic group whose ring member is 5-10.

“Substituent” as used herein refers to a halogen atom, a hydroxy group, an amino group, an oxo group, a cyano group, a nitro group, a carboxyl group, an aminocarbonyl group, a thioamide group, a C1-C6 alkyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy C1-C6 alkoxy group, a halogeno C1-C6 alkyl group, a halogeno C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, an unsaturated heterocyclic group, a saturated heterocyclic group, a nitrogen-containing saturated heterocyclic group, a nitrogen-containing saturated heterocyclic carbonyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C2-C7 alkoxycarbonyl group, a C1-C14 acyloxy group, C7-C13 aralkyloxy group and the like.

“Halogen atom” as used herein refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

“C1-C6 alkyl group” as used herein refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a hexyl group and the like.

“C2-C6 alkynyl group” as used herein refers to an unsaturated straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one triple bond, e.g., ethynyl, 1- or 2-propynyl group, 1-, 2- or 3-butynyl group, 1-methyl-2-propynyl group and the like.

“C3-C6 cycloalkyl group” as used herein refers to a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.

“C1-C6 alkoxy group” as used herein refers to an oxy group to which a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms is bonded, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group and the like.

“C1-C6 alkoxy C1-C6 alkoxy group” as used herein refers to a C1-C6 alkoxy group in which one of the hydrogen atom of the C1-C6 alkoxy group is substituted with a C1-C6 alkoxy group, for example, a methoxymethoxy group, a methoxyethoxy group, a methoxy propoxy group, an ethoxymethoxy group, an ethoxyethoxy group, a propoxy methoxy group and the like.

“halogeno C1-C6 alkyl group” as used herein refers to a C1-C6 alkyl group in which one or more hydrogen atoms are substituted with a halogen atom, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, a fluoroethyl group, 1,1,1-trifluoroethyl group, a mono fluoro-n-propyl group, a perfluoro-n-propyl group, a perfluoro isopropyl group and the like.

“C6-C14 aromatic hydrocarbon group” as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, for example, a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, a fluorenyl group and the like.

“Unsaturated heterocyclic group” as used herein refers to a monocyclic or polycyclic unsaturated heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom (preferably 1 to 4, more preferably 1 to 3). The unsaturated heterocyclic group includes a fully unsaturated heterocyclic group (a fully unsaturated heterocyclic group) and a partially unsaturated heterocyclic group (a partially unsaturated heterocyclic group).

A fully unsaturated heterocyclic group includes, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl, a furanyl (a furyl group), an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiophenyl group (a thienyl group), a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a pyridinyl group (a pyridyl group), a pyrimidinyl group (pyrimidyl group), a pyrazinyl group (a pyrazyl group), a pyridazinyl group, an indolyl group, an isoindolyl group, an indazolyl group (a benzpyrazol group), a benzimidazolyl group, a benzotriazolyl group, an azaindolyl group, a pyrrolopyridinyl group, an imidazopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrrolopyrimidinyl group, an imidazopyrimidinyl group, a pyrazolopyrimidinyl group, a benzofuranyl group, a benzoxazolyl group, a benzothiophenyl group (a benzothienyl group), a benzothiazolyl group, a benzothiadiazolyl group, a benzofuranyl group (a benzofuryl group), a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalyl group and the like.

A partially unsaturated heterocyclic group includes, for example, a dihydropyranyl group, a dihydro triazolyl group, a dihydrofuranyl group, a dihydrooxadiazolyl group, a dihydroquinolyl group, a dihydroquinazolinyl group, an indolinyl group, a tetrahydroisoquinolyl group, a methylenedioxyphenyl group, an ethylenedioxy phenyl group, a dihydrobenzofuranyl group, a dihydro-benzoxazolyl group, a dihydropyridooxazinyl group and the like.

“Saturated heterocyclic group” as used herein refers to a single or polycyclic fully saturated heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom (preferably 1 to 4, more preferably 1 to 3), and includes, for example, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperazinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothiophenyl group, a thiazolidinyl group, an oxazolidinyl group and the like.

“Nitrogen-containing saturated heterocyclic group” as used herein refers to a saturated heterocyclic group having one or more nitrogen atoms, which optionally includes a hetero atom other than nitrogen atom, and includes, for example, a morpholino group.

“Nitrogen-containing saturated heterocyclic carbonyl group” as used herein refers to a carbonyl group to which a nitrogen-containing saturated heterocyclic group is bonded, and includes, for example, a morpholinocarbonyl group.

“C1-C14 acyl group”, as used herein refers to a carbonyl group to which a hydrogen atom, a C1-C6 alkyl group, a C6-C14 aromatic hydrocarbon group or an unsaturated heterocyclic group is bonded, and includes, for example: a formyl group; a (C1-C6 alkyl) carbonyl group such as an acetyl group, a propanoyl group, a butanoyl group; a (C3-C6 cycloalkyl) carbonyl group such as a cyclopropanoyl group, a cyclobutanoyl group; or a (C6-C13) arylcarbonyl group such as a benzoyl group, a naphthyl carbonyl group, a fluorenylcarbonyl group.

“C1-C14 acylamino group” as used herein refers to an amino group in which one or two hydrogen atoms are substituted with a C1-C14 acyl group, and includes, for example, an acetylamino group, a propanoylamino group, a butanoylamino group, a cyclopropanoyl amino group.

“C2-C7 alkoxycarbonyl group”, as used herein refers to a carbonyl group to which a C1-C6 alkoxy group is bonded, and includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, a tert-butoxycarbonyl group and the like.

“C1-C14 acyloxy group” as used herein refers to, for example, a formyloxy group; a (C1-C6 alkyl)carbonyloxy group such as a methyl carbonyloxy group, an ethyl carbonyloxy group, an n-propyl carbonyloxy group, an isopropylcarbonyloxy group, an n-butylcarbonyloxy group, an iso-butylcarbonyloxy group, a tert-butylcarbonyloxy group, an n-pentylcarbonyloxy group, an iso-pentylcarbonyloxy group, a hexylcarbonyloxy group and the like; a (C3-C6 cycloalkyl)carbonyloxy group such as a cyclopropanoyloxy group, a cyclobutanoyloxy group and the like; a (C6-C13 aryl)carbonyloxy group such as a phenylcarbonyloxy group, naphthylcarbonyloxy group, a fluorenylcarbonyloxy group and the like.

“C7-C13 aralkyloxy group” as used herein refers to an alkylloxy group in which one hydrogen atom is substituted with an aryl group, and includes, for example, a benzyloxy group, a phenethyloxy group, a naphthylmethyloxy group, a fluorenylmethyloxy group and the like.

“Saturated or partially unsaturated hydrocarbon ring” as used herein refers to a monocyclic or polycyclic saturated or partially unsaturated hydrocarbon ring, and includes, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, a cyclooctadiene ring and the like.

“Saturated or partially unsaturated heterocyclic ring” as used herein refers to a monocyclic or polycyclic saturated or partially unsaturated heterocyclic a ring having a hetero atom selected from a nitrogen atoms a sulfur atom and an oxygen atom, and includes, for example, an oxirane ring, an azetidine ring, a pyrrolidine ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a tetrahydrofuran ring, a tetrahydropyran ring, a dioxane ring, a tetrahydrothiophene ring, a dihydropyran ring, a dihydrofuran ring and the like.

“Spiro heterocyclic group” as used herein refers to a saturated or unsaturated spiro heterocyclic group having a spiro carbon atom and a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom, and includes, for example, a 2-oxa-6-azaspiro[3.4]octanyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group and the like.

“Bridged heterocyclic group” as used herein refers to a bridged heterocyclic group having more than one ring, which have two bridgehead carbons and a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom, and includes, for example, a 3-oxa-8-azabicyclo[3.2.1]octanyl group, an 8-oxa-3-azabicyclo[3.2.1]octanyl group and the like.

In the compounds represented by the formula (I) of the present specification, X¹ is an oxygen atom or a sulfur atom. X¹ is preferably an oxygen atom.

In the compounds represented by the formula (I) of the present specification, X² is an oxygen atom or —NH—. X² is preferably an oxygen atom.

In the compounds represented by the formula (I) of the present specification, X³ is —NH— or an oxygen atom. X³ is preferably —NH—.

In the compounds of the formula (I), X⁴ is a hydrogen atom or a C1-C6 alkyl group.

“C1-C6 alkyl group” represented by X⁴ is preferably a C1-C3 alkyl group, more preferably a methyl group.

X⁴ is preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom.

In the compounds of the formula (I), R¹ is, —C(R¹¹)(R¹²)— or —C(═CH₂)—.

In —C(R¹¹)(R¹²)—, R¹¹ and R¹² are the same or different, and are a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively taken together with the carbon atoms to which they attach to form a saturated hydrocarbon ring having 3 to 8 carbon atoms.

“Halogen atom” represented by R¹¹ and R¹² is preferably a fluorine atom, a chlorine atom, a bromine atom, more preferably a fluorine atom.

“C1-C6 alkyl group” indicated in R¹¹ and R¹² is preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group, more preferably a methyl group.

“Saturated hydrocarbon ring having 3 to 8 carbon atoms”, which is formed by combining R¹¹ and R¹² together with the carbon atoms to which they attached, is preferably a monocyclic saturated hydrocarbon ring of 3 to 6 carbon atoms, and more preferably a cyclopropane ring.

Preferably, R¹¹ is a halogen atom, a hydroxy group, or a C1-C6 alkyl group, and R¹² is a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively R¹¹ and R¹² are taken together with the carbon atoms to which they are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms. More preferably, R¹¹ is a C1-C6 alkyl group, and R¹² is a hydrogen atom, and more preferably R¹¹ is a methyl group, and R¹² is a hydrogen atom.

R¹ is preferably —C(R¹¹)(R¹²)—, R¹¹ is a halogen atom, a hydroxy group, or a C1-C6 alkyl group, and R¹² is a hydrogen atom, a halogen atom, hydroxy group, or a C1-C6 alkyl group, alternatively R¹ and R¹² are taken together with the carbon atoms to which they are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms. More preferably, —C(R¹¹)(R¹²)—, and, R¹ is a C1-C6 alkyl group, R¹² is a hydrogen atom. Even more preferably, it is —CH(CH₃)—.

In the compounds of the formula (I), R² is a C6-C14 aromatic hydrocarbon group or a 9-10 membered fully unsaturated heterocyclic group.

“C6-C14 aromatic hydrocarbon group” represented by R² is preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group or a naphthyl group, even more preferably a phenyl group.

Furthermore, “fully unsaturated heterocyclic group having 9-10 membered” represented by R² is preferably a bicyclic 9-10 membered fully unsaturated heterocyclic group having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a bicyclic 9-10 membered fully unsaturated heterocyclic group having 1-2 hetero atoms selected from a nitrogen atom and a sulfur atom, even more preferably a benzothiophenyl group, a benzothiazolyl group, a quinolyl group.

In the compounds of the formula (I), R² may be unsubstituted or may have a substituent. Further, when R² has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, R² may form a 4 to 8-membered saturated or partially unsaturated hydrocarbon ring or a heterocyclic ring having substituent(s), wherein the substitutes are fused to form a ring together with the carbon atom to which they are attached.

When R² has a substituent, the substituted position of the substituent is not particularly limited, but, for example, preferably 2, 3, 5, or 6-position when R² is a phenyl group. Furthermore, the number of substituent is not particularly limited, but preferably zero, i.e. it is unsubstituted or 1-4, and more preferably 1-4 or 1-3. When the number of substituents is two or more, the types of the substituent may be the same or different.

In the compounds of formula (I), preferably, R² may be substituted with the “substituent”, more preferably, R² may be substituted with R²¹. Also, preferably, when R² has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atom to which they are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring optionally substituted with Rz.

R²¹, which can be substituted at R², is a halogen atom, an aminocarbonyl group, a cyano group, a C1-C6 alkyl group which may be substituted with Rx, a C3-C6 cycloalkyl group which may be substituted with Rx, a C2-C6 alkynyl group which may be substituted with Rx, a C6-C14 aromatic hydrocarbon group which may be substituted with Ry, or an unsaturated 5-10 membered heterocyclic ring which may be substituted with Rz.

The position at which R²¹ is a substituted is not particularly limited, but, for example, preferably 2, 3, 5, or 6-position when R² is a phenyl group. Furthermore, the number of the substituent R²¹ is not particularly limited, but preferably zero, i.e. it is unsubstituted, or 1-4, more preferably 1-4 or 1-3. When the number of the substituent R²¹ is two or more, the types of the substituent may be the same or different.

“Halogen atom” indicated in R²¹ is preferably a fluorine atom, a chlorine atom, or a bromine atom.

“C1-C6 alkyl group” in the “C1-C6 alkyl group which may be substituted with Rx” indicated in R²¹ is preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group.

The substituent Rx in the “C1-C6 alkyl group which may be substituted with Rx” indicated in R²¹ is a halogen atom or a C6-C14 aromatic hydrocarbon group. The substituent Rx is preferably a halogen atom, more preferably a fluorine atom. The number of Rx which is substituted at C1-C6 alkyl group is not particularly limited, but preferably zero, i.e., unsubstituted, or 1-3. When the number of substituent Rx is 2 or more, the types of the substituent may be the same or different.

“C3-C6 cycloalkyl group” in the “C3-C6 cycloalkyl group which may be substituted with Rx” indicated in R²¹ is preferably a cyclopropyl group.

Rx in the “C3-C6 cycloalkyl group which may be substituted with Rx” indicated in R²¹ is a halogen atom as mentioned above, or a C6-C14 aromatic hydrocarbon group, preferably a halogen atom, more preferably a fluorine atom. The number of Rx substituted at the C3-C6 cycloalkyl group is not particularly limited, but preferably zero, i.e. it is unsubstituted, or 1, more preferably 0. When the number of substituents Rx is 2 or more, the types of the substituent may be the same or different.

“C2-C6 alkynyl group” in the “C2-C6 alkynyl group which may be substituted with Rx” indicated in R²¹ is preferably a C2-C4 alkynyl group, more preferably an ethynyl group.

The substituent Rx in the “C2-C6 alkynyl group may be substituted with Rx” indicated in R²¹ is a halogen atom as mentioned above, or a C6-C14 aromatic hydrocarbon group, preferably a C6-C14 aromatic hydrocarbon group, more preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group.

The number of Rx substituted at the C2-C6 alkynyl group is not particularly limited, but preferably zero, i.e. it is unsubstituted, or 1, more preferably 1. When the number of the substituents Rx is 2 or more, the types of the substituent may be the same or different.

“C6-C14 aromatic hydrocarbon group” in the “C6-C14 aromatic hydrocarbon group which may be substituted with Ry” indicated in R²¹ is preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group.

The substituent Ry in the “C6-C14 aromatic hydrocarbon group which may be substituted with Ry” indicated in R²¹ is a halogen atom or a C1-C6 alkoxy group.

A halogen atom indicated in Ry is preferably a fluorine atom or chlorine atom. Also, a C1-C6 alkoxy group indicated in Ry is preferably a C1-C3 alkoxy group, more preferably a methoxy group. The substituent Ry in the “C6-C14 aromatic hydrocarbon group which may be substituted with Ry” indicated in R²¹ is preferably a fluorine atom, a chlorine atom, or a C1-C3 alkoxy group, more preferably a fluorine atom, a chlorine atom or a methoxy group. The number of Ry substituted in the C6-C14 aromatic hydrocarbon group is not particularly limited, but preferably zero, i.e. unsubstituted, or it is 1 or 2. When the number of the substituents Ry is 2 or more, the types of substituent may be the same or different.

“5 to 10-membered unsaturated heterocyclic group” in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rz” indicated in R²¹ is preferably a fully or partially unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom, more preferably a monocyclic 5-6 membered unsaturated heterocyclic group having 1-3 nitrogen atoms or an oxygen atom. Preferably, it is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidyl group, an oxazolyl group, a dihydropyridooxazinyl group, more preferably, a pyrazolyl group, a pyridyl group, a pyrimidyl group, an oxazolyl group, a dihydropyridooxazinyl group, more preferably a pyrazolyl group.

The substituent Rz in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rz” indicated in R²¹ is a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, or a nitrogen-containing saturated heterocyclic carbonyl group.

“Halogen atom” indicated in Rz is preferably a fluorine atom or a chlorine atom.

“C1-C6 alkyl group” indicated in Rz is preferably a C1-C3 alkyl group, more preferably a methyl group, or an ethyl group.

“Halogeno C1-C6 alkyl group” indicated in Rz is preferably a halogeno C1-C3 alkyl group, more preferably a difluoromethyl group or a trifluoromethyl group.

“C3-C6 cycloalkyl group” indicated in Rz is preferably a cyclopropyl group or a cyclobutyl group.

“C1-C6 alkoxy group” indicated in Rz is preferably a C1-C3 alkoxy group, more preferably a methoxy group.

“C6-C14 aromatic hydrocarbon group” indicated in Rz is preferably a phenyl group.

“Nitrogen-containing saturated heterocyclic group” represented by Rz is preferably a morpholino group or a piperidinyl group.

“Nitrogen-containing saturated heterocyclic carbonyl group” indicated in Rz is preferably a morpholinocarbonyl group.

The substituent Rz in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rz” is preferably a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a phenyl group, a morpholino group, a piperidinyl group, or a morpholinocarbonyl group, more preferably a C1-C6 alkyl group, more preferably a methyl group. The number of Rz which is substituted at the 5 to 10-membered unsaturated heterocyclic group is not particularly limited, but preferably zero, i.e. unsubstituted, or preferably 1 or 2. When the number of the substituent Rz is 2 or more, the type of the substituent may be the same or different.

R²¹, which can be substituted at R², is preferably, a halogen atom, an aminocarbonyl group, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a C2-C6 alkynyl group (optionally substituted with a C6-C14 aromatic hydrocarbon group) a C6-C14 aromatic hydrocarbon group (optionally substituted with a group selected from a halogen atom and a C1-C6 alkoxy group), or a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, and a nitrogen-containing saturated heterocyclic carbonyl group).

More preferably, a halogen atom, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (optionally substituted with a group selected from the group consisting of a halogen atom or a C1-C6 alkoxy group), or monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group).

More preferably, a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6-membered unsaturated heterocyclic group having 1 to 3 of a nitrogen atom(s) (optionally substituted with a C1-C6 alkyl group).

More preferably, a halogen atom or a C1-C6 alkyl group.

In the compounds of the formula (I), when the number of the substituents at R² is 2 or more, and there are two substituents at the carbons which are adjacent each other on the aromatic hydrocarbon ring, “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which may have substituent(s)”, which is formed by combining the substituents and the carbon atom to which they are attached, is a ring, for example a ring fused to a benzene ring.” Saturated or partially unsaturated 4 to 8-membered hydrocarbon ring or heterocyclic ring” in the “4-8 membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring, which may have substituent(s)” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring, or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms, more preferably, a saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms, more preferably, a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 6 carbon atoms, or a monocyclic 4-6 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen atom, a sulfur atom, and an oxygen atom, and even more preferably, a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbon atoms, more preferably a saturated hydrocarbon ring having 5 carbon atoms.

The substituent Rz in the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring optionally substituted with Rz” is, as mentioned above, a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, or a nitrogen-containing saturated heterocyclic carbonyl group, preferably a C1-C6 alkyl group, and more preferably, a C1-C3 alkyl group, and even more preferably, a methyl group. The number of Rz which substitutes at a saturated or partially unsaturated hydrocarbon ring or heterocyclic ring is not particularly limited, but preferably zero, i.e., unsubstituted, or it is one, more preferably it is zero, i.e., unsubstituted. When the number of the substituents Rz is 2 or more, the type of substituent may be the same or different.

“Saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring optionally substituted with Rz” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms, which is optionally substituted with Rz, or a monocyclic 4-8 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, more preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which may be substituted with a C1-C6 alkyl group) or a monocyclic saturated or partially unsaturated 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a C1-C6 alkyl group), more preferably a saturated or partially unsaturated monocyclic hydrocarbon ring having 4 to 8 carbon atoms (optionally substituted with a C1-C6 alkyl group), more preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbon atoms (optionally substituted with a C1-C6 alkyl group).

In the compounds represented by formula (I), a fused ring, which is formed when the compound has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring of R², is for example, a dihydro-indene ring, a tetrahydronaphthalene ring, a dihydrobenzofuran ring.

In the compounds represented by formula (I), R² is preferably a C6-C14 aromatic hydrocarbon group or a bicyclic fully unsaturated 9-10 membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms, and R² may be substituted with R²¹, and when R² has two substituents on the carbon atom adjacent each other on the aromatic hydrocarbon ring, R² may be a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (optionally substituted with a C1-C6 alkyl group) wherein the substituents are fused together with the carbon atom to which each of the substituent is bonded, or a monocyclic 4-8 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms (optionally substituted with a C1-C6 alkyl group); and

R²¹ is a halogen atom, an aminocarbonyl group, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a C2-C6 alkynyl group (optionally substituted with a C6-C14 aromatic hydrocarbon group), a C6-C14 aromatic hydrocarbon group (optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkoxy group), or a monocyclic or bicyclic 5-10 membered unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, and a nitrogen-containing saturated heterocyclic carbonyl group).

In the compounds represented by formula (I), R² is more preferably a C6-C14 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atom adjacent each other on the aromatic hydrocarbon ring, R² may form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (optionally substituted with a C1-C6 alkyl group) wherein the substituents are fused together with the carbon atom to which each of the substituent is bonded;

R²¹ is a halogen atom, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (optionally substituted with a group selected from the group consisting of a halogen atom a C1-C6 alkoxy group), or a monocyclic or bicyclic 5-10 membered unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group).

Also, in the compounds represented by formula (I), R² is more preferably a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atom adjacent each other on the aromatic hydrocarbon ring, R² may form a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbon atoms (optionally substituted with a C1-C6 alkyl group) wherein the substituents are fused together with the carbon atom to which each of the substituents is bonded; and

R²¹ is a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6-membered unsaturated heterocyclic ring having 1-3 nitrogen atom(s) (optionally substituted with a C1-C6 alkyl group).

Also, in the compounds represented by formula (I), R² is especially preferably a phenyl group or a naphthyl group (optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkyl group); an indanyl group (2,3-dihydro-1H-indenyl group); or a tetrahydronaphthyl group.

In the compounds represented by formula (I), R³ is a C6-C14 aromatic hydrocarbon group or a 5 to 10-membered fully unsaturated heterocyclic group.

“C6-C14 aromatic hydrocarbon group” indicated in R³ is preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group, or a naphthyl group, particularly preferably a phenyl group.

“5 to 10-membered fully unsaturated heterocyclic group” indicated in R³ is a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably, a monocyclic or bicyclic 5 to 7-membered fully unsaturated heterocyclic group having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, particularly preferably a monocyclic 5 to 6-membered fully unsaturated heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms. Preferably, an imidazolyl group, a pyridyl group, a thiophenyl group, an indolyl group, an indazolyl group, a benzopyranyl group, a benzotriazolyl group, a benzothiadiazolyl group, an isoxazolyl group, a quinolyl group, more preferably an imidazolyl group, a pyridyl group, a thiophenyl group, an indolyl group, an indazolyl group, a benzopyranyl group, a benzotriazolyl group, a benzothiadiazolyl group, a quinolyl group, more preferably a pyridyl group, a thiophenyl group, an indolyl group, an indazolyl group, a benzopyranyl group, a benzotriazolyl group, a quinolyl group, more preferably a pyridyl group.

In the compounds represented by formula (I), R³ may be unsubstituted or may have a substituent. Also, when R³ has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, R³ may form a 4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring, which may be substituted, wherein the substituents are fused together with the carbon atom to which each of the substituents is bonded; and

When R³ has a substituent, the position of the substituent is not particularly limited. Although the number of the substituent is not limited, it is particularly preferably 0, i.e. unsubstituted. Alternatively, the number of the substituent is 1 to 4, more preferably 1 to 3. When the number of substituent is two or more, the types of the substituent may be the same or different.

In the compounds represented by formula (I), preferably R³ may be substituted with the “substituent”, more preferably R³ may be substituted with R³¹. Also, preferably, when R³ has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, R³ may form a 4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring, which may be substituted with Rc, wherein the substituents are fused together with the carbon atom to which each of the substituents is bonded.

R³¹, which can be substituted at R³, is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group which may be substituted with Ra, an amino group which may be substituted with Ra, a C3-C6 cycloalkyl group which may be substituted with Rb, a C1-C6 alkoxy group which may be substituted with Rb, a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group which may be substituted with Rb, a C6-C14 aromatic hydrocarbon ring which may be substituted with Rb, an 5 to 10-membered unsaturated heterocyclic ring which may be substituted with Rc, an aminocarbonyl group which may be substituted with Rd and Re, or —S(═O)₂Rf.

Although the number of the substituent is not limited, it is particularly preferably 0, i.e. unsubstituted. Alternatively, the number of the substituent is 1 to 4, more preferably 1 to 3. When the number of substituent is two or more, the types of the substituent may be the same or different.

“Halogen atom” indicated in R³¹ is preferably a fluorine atom, a chlorine atom, or a bromine atom, more preferably a chlorine atom, or a bromine atom.

“C1-C6 alkyl group” of “a C1-C6 alkyl group which may be substituted with Ra” indicated in R³¹ is preferably a C1-C3 alkyl group, more preferably a methyl group.

The substituent Ra of “a C1-C6 alkyl group which may be substituted with Ra” indicated in R³¹ is a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group.

“Halogen atom” indicated in Ra is preferably a fluorine atom.

“C1-C14 acyl group” indicated in Ra is preferably an acetyl group.

“C1-C14 acyloxy group” indicated in Ra is preferably an acetyloxy group.

“C2-C6 alkynyl group” indicated in Ra is preferably an ethynyl group, 1-propynyl group.

“C1-C6 alkoxy C1-C6 alkoxy group” indicated in Ra is preferably a methoxymethoxy group.

The substituent Ra of “a C1-C6 alkyl group may be substituted with Ra” indicated in R³¹ is preferably a halogen atom, a hydroxy group, a C1-C6 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group, more preferably a halogen atom, or a hydroxy group. Although the number of Ra which is substituted at the C1-C6 alkyl is not particularly limited, preferably zero, i.e. unsubstituted, or one or more. When the number of the substituents Ra is 2 or more, the types of the substituent may be the same or different.

Ra of “an amino group optionally substituted with Ra” indicated in R³¹ is a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group, preferably a C1-C14 acyl group, more preferably an acetyl group.

The number of Ra substituted at the amino group is not particularly limited, preferably zero, i.e. unsubstituted, or is 1, more preferably 0.

“C3-C6 cycloalkyl group” in the “C3-C6 cycloalkyl group optionally substituted with Rb” indicated in R³¹ is preferably a cyclopropyl group.

Rb in the “C3-C6 cycloalkyl group optionally substituted with Rb” indicated in R³¹ is a halogen atom, an amino group, or a C1-C6 alkoxy group.

“Halogen atom” indicated in Rb is preferably a fluorine atom.

“C1-C6 alkoxy group” indicated in Rb is preferably a C1-C3 alkoxy group, more preferably a methoxy group.

Rb in the “C3-C6 cycloalkyl group optionally substituted with Rb” indicated in R³¹ is preferably an amino group. The number of Rb substituting at the C3-C6 cycloalkyl group is not particularly limited, preferably zero, i.e. unsubstituted, or is 1, more preferably 0. When the number of substituents Rb is two or more, the types of the substituent may be the same or different.

“C1-C6 alkoxy group” in the “C1-C6 alkoxy group optionally substituted with Rb” indicated in R³¹ is preferably a C1-C3 alkoxy group, more preferably a methoxy group.

Rb in the “C1-C6 alkoxy group optionally substituted with Rb” indicated in R³¹ is, as mentioned above, a halogen atom, an amino group, or a C1-C6 alkoxy group, preferably a halogen atom, more preferably a fluorine atom. Although number of Rb substituent to a C1-C6 alkoxy group is not limited, it is zero, i.e. unsubstituted, or one or two. When the number of substituent Rb is two or more, the types of the substituent may be the same or different.

“C2-C7 alkoxycarbonyl group” indicated in R³¹ is preferably a C2-C4 alkoxycarbonyl group, more preferably a methoxycarbonyl group.

“C1-C14 acyl group” in the “C1-C14 acyl group optionally substituted with Rb” indicated in R³¹ is preferably an acetyl group.

Rb in the “C1-C14 acyl group optionally substituted with Rb” indicated in R³¹ is, as mentioned above, a halogen atom, an amino group, or a C1-C6 alkoxy group, preferably a halogen atom, more preferably a fluorine atom. Although number of Rb substituent at a C1-C14 acyl group is not limited, it may be zero, i.e. unsubstituted, or one to three. When the number of substituents Rb is two or more, the types of the substituent may be the same or different.

“Thioamide group” indicated in R³¹ is preferably —C(═S)—NH₂.

“C6-C14 aromatic hydrocarbon group” in the “C6-C14 aromatic hydrocarbon group optionally substituted with Rb” indicated in R³¹ is preferably a C6-C10 aromatic hydrocarbon group, and more preferably a phenyl group.

The substituent Rb in the “C6-C14 aromatic hydrocarbon group optionally substituted with Rb” indicated in R³¹ is, as mentioned above, a halogen atom, an amino group, or a C1-C6 alkoxy group, and preferably a halogen atom or a C1-C3 alkoxy group, and more preferably a halogen atom, and more preferably a fluorine atom. Although the number of Rb substituting at a C6-C14 aromatic hydrocarbon group is not particularly limited, it is preferably zero, i.e. unsubstituted, or it is one. When the number of the substituents Rb is 2 or more, the type of groups may be the same or different.

“5 to 10-membered unsaturated heterocyclic group” in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rc” indicated in R³¹ is preferably a monocyclic or bicyclic 5-10 membered fully or partially unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic 5 to 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferably it is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a tetrazolyl group, an isoxazolyl group, an oxadiazolyl group, a dihydro oxadiazolyl group, preferably a pyrazolyl group, a 1,3,4-oxadiazolyl group, a 2,3-dihydro-1,3,4-oxazolyl group.

The substituent Rc in the “5-10 membered unsaturated heterocyclic group optionally substituted with one or more of Rc” indicated in R³¹ is a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl, or a C1-C14 acylamino group, a C1-C14 acyloxy group, or a C7-C13 aralkyloxy group.

“Halogen atom” indicated in Rc is preferably a fluorine atom.

“C1-C6 alkyl groups optionally substituted with a hydroxy group” indicated in Rc is preferably a C1-C3 alkyl group optionally substituted with a hydroxy group, and more preferably a methyl group or a hydroxyethyl group.

“Halogeno C1-C6 alkyl group” represented by Rc is preferably a halogeno C1-C3 alkyl group, more preferably a trifluoromethyl group, a difluoroethyl group.

“C1-C14 acyl group” indicated in Rc is preferably an acetyl group or a cyclopropanoyl group.

“C1-C14 acylamino group” indicated in Rc is preferably an acetylamino group.

“C1-C14 acyloxy group” indicated in Rc is preferably an acetyloxy group.

“C7-C13 aralkyloxy group” indicated in Rc is preferably a benzyloxy group.

Rc in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rc” indicated in R³¹ is preferably a halogen atom, a C1-C6 alkyl group, or an oxo group, more preferably a C1-C6 alkyl group or an oxo group, more preferably a C1-C6 alkyl group. Although the number of Rc substituting at 5 to 10-membered unsaturated heterocyclic group is not particularly limited, it is preferably zero, i.e. unsubstituted, or preferably it is one or more than 2, more preferably it is zero. When the number of the substituents Rc is 2 or more, the type of groups may be the same or different.

“An amino carbonyl group optionally substituted with Rd and Re” indicated in R³¹ is specifically represented by the following group (II).

Rd and Re are the same or different and represent: a hydrogen atom; a hydroxy group; a C7-C13 aralkyloxy group; or C1-C6 alkyl group optionally substituted with hydroxyl groups; alternatively taken together with a nitrogen atom which is adjacent to Rd and Re to form a saturated or unsaturated 4 to 10-membered heterocyclic ring group optionally substituted with an amino group, a spiro heterocyclic ring group, or a bridged heterocyclic ring group.

“C7-C13 aralkyloxy group” indicated in Rd or Re is preferably a benzyloxy group.

“C1-C6 alkyl group optionally substituted with hydroxy groups” indicated in Rd or Re is preferably a C1-C3 alkyl group optionally substituted with a hydroxy group, more preferably a methyl group, or a hydroxyethyl group.

“A saturated heterocyclic group” in the “4 to 10-membered saturated heterocyclic group optionally substituted with an amino group” in Rd or Re is preferably a monocyclic or bicyclic 4 to 10-membered saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, preferably a 5 to 6-membered monocyclic saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, more preferably an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a morpholino group.

“An unsaturated heterocyclic group” in the “4 to 10-membered saturated or unsaturated heterocyclic group optionally substituted with an amino group”, which is formed together with Rd or Re and the adjacent nitrogen atoms, is preferably a monocyclic or bicyclic or 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, more preferably a monocyclic 5 to 6-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, particularly preferably a pyrrolyl group.

“Spiroheterocyclic group” formed together with Rd or Re and the adjacent nitrogen atom is preferably a monosupiro heterocyclic group, more preferably an oxoazaspirononanylcarbamoyl group, or an azasupirooctanylcarbamoyl group.

“Bridged heterocyclic group” formed together with Rd or Re and the adjacent nitrogen atom indicated is preferably a bicyclic bridged heterocyclic group, more preferably an oxoazabicyclooctanylcarbamoyl group.

The substituents Rd and Re in the “aminocarbonyl group optionally substituted with Rd and Re” indicated in R³¹ are preferably the same or different, and present a hydroxy group or a C1-C6 alkyl group, alternatively taken together with the adjacent nitrogen atom to form a monocyclic 5 to 6-membered saturated heterocyclic group, which may be substituted with an amino group, having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a monosupiro heterocyclic group or a bicyclic bridged heterocyclic group.

“An amino carbonyl group optionally substituted with Rd and Re” indicated in R³¹ is preferably a —CONH₂ group, (a mono or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyamino group, a (C7-C13 aralkyl)oxyaminocarbonyl group, or a cyclicaminocarbonyl group, more preferably a —CONH₂ group, (a mono or di-C1-C3 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group, a benzyloxycarbonylgroup, a pyrrolidin-1-ylcarbonyl group, a piperidin-1-ylcarbonyl group, a piperazin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, an azetidin-1-ylcarbonyl group, an oxo azabicyclooctanylcarbonyl group, an oxo azaspiro nonanylcarbonyl group, an azaspirooctanylcarbonyl group, more preferably a —CONH₂ group, a dimethylaminocarbonyl group, or a pyrrolidin-1-ylcarbonyl group.

Rf of “—S(═O)₂Rf” indicated in R³¹ is an amino group, a C1-C6 alkyl group, or a 4 to 10-membered saturated heterocyclic group.

C1-C6 alkyl group indicated in Rf is preferably a C1-C3 alkyl group, more preferably a methyl group.

A 4 to 10-membered saturated heterocyclic group indicated in Rf is preferably a monocyclic or bicyclic 4 to 10-membered saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic 5 to 6-membered saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, more preferably a pyrrolidinyl group, a piperidino group, or a piperazinyl group.

“—S(═O)₂Rf” indicated in R³¹ is preferably an aminosulfonyl group, a methylsulfonyl group, or a piperidinosulfonyl group.

R³¹ which may be substituted with R³ is preferably a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group (which may be substituted with a C1-C14 acyl group), a C3-C6 cycloalkyl group (which may be substituted with an amino group), a C1-C6 alkoxy group (which may be substituted with halogen atoms), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (which may be substituted with halogen atoms), a C6-C14 aromatic hydrocarbon group (which may be substituted with a group selected from the group consisting of a halogen atom, an amino group and a C1-C6 alkoxy group), monocyclic or bicyclic 5 to 10 membered unsaturated heterocyclic ring having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which may be substituted with a group consisting of a halogen atom, an oxo group, and a C1-C6 alkyl group), an aminocarbonyl group optionally substituted with Rd and Re (wherein, Rd and Re are the same or different, and present a hydrogen atom, a hydroxy group, a C7-C13 aralkyloxy group, or a C1-C6 alkyl group which may be substituted with a hydroxyl group, alternatively they are taken together with the adjacent nitrogen atom to form a monocyclic or bicyclic 4-10 membered saturated or unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a spiro heterocyclic group, or a bridged heterocyclic group), or —S(═O)₂Rf (wherein Rf is an amino group, a C1-C6 alkyl group, or a 4-10 membered saturated heterocyclic group).

More preferably, it is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group, a C3-C6 cycloalkyl group (which may be substituted with an amino group), a C1-C6 alkoxy group (which may be substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (which may be substituted with a halogen atom), C6-C10 aromatic hydrocarbon group (which may be substituted with a halogen atom), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which may be substituted with a group selected from the group consisting of a C1-C6 alkyl group and an oxo group), a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group, a (C7-C13 aralkyl)oxyaminocarbonyl group, a cyclic aminocarbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl a group.

More preferably, it is a halogen atom, an amino group, a C1-C6 alkyl group (which may be substituted with a group selected from the group consisting of a halogen atom and a hydroxy group) a C1-C6 alkoxy group (which may be substituted with halogen atoms), a monocyclic 5 or 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono or di C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino group.

More preferably, it is a halogen atom, an amino group, a C1-C6 alkoxy group, or a —CONH₂ group.

When the compound of the formula (I) has two or more substituents on R³ and two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring of R³, the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which may be substituted”, which is formed with the carbon atoms to which they are attached, is the ring, such as a ring fused to a benzene ring. “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring” in the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which may be substituted” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms, or 4 to 8-membered saturated or partially unsaturated hetero ring having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, more preferably, a monocyclic 4 to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic 6-membered saturated or partially unsaturated heterocyclic ring having one or two oxygen atom(s).

Substituent Rc in the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which is optionally substituted with Rc” is a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group which is optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group, or a C7-C13 aralkyloxy group, preferably a hydroxy group, an amino group, an oxo group, or a C1-C6 alkyl group which is optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acyloxy group, more preferably a hydroxy group, or a C1-C6 alkyl group. The number of Rc which substitutes at a saturated or partially unsaturated hydrocarbon ring or heterocyclic ring is not particularly limited, but is preferably 1 to 3. When the number of substituent Rc is 2 or more, the type of groups may be the same or different.

“4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which is optionally substituted with Rc” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group and a C7-C13 aralkyloxy group), a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom from sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group and a C7-C13 aralkyloxy group).

More preferably, a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, and a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group).

More preferably, a monocyclic 4 to 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (which is optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acylamino group and a C1-C14 acyloxy group).

More preferably, a monocyclic 6-membered saturated or partially unsaturated heterocyclic ring having 1 or two oxygen atom(s) (which is optionally substituted with a group selected from the group consisting of a hydroxyl group and a C1-C6 alkyl group).

In the compounds represented by the formula (I), a fused ring which is formed when there are two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring of R³, is for example, a chroman ring, a dihydrobenzoxazine ring, a dihydroindene ring, an indoline ring, a tetrahydroquinoxaline ring, a dihydrobenzodioxane ring, a tetrahydronaphthalene ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, a dihydrobenzothiophene ring, an isoindoline ring, a dihydroisobenzofuran ring, a dihydrobenzoimidazole ring, and the like.

In the compounds represented by the formula (I), R³ is preferably a C6-C14 aromatic hydrocarbon group, or a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1 to 3 heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ may be substituted with R³¹, or when R³ has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group consisting of the group selected from a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group, and a C7-C13 aralkyloxy group), or, a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl groups, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group, a C7-C13 aralkyloxy group);

R³¹ is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group (optionally substituted with a C1-C14 acyl group), a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with halogen atoms), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), a C6-C14 aromatic hydrocarbon group (optionally substituted with a group selected from the group consisting of a halogen atom, an amino group and a C1-C6 alkoxy group), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, an oxo group, and a C1-C6 alkyl group), an amino carbonyl group optionally substituted with Rd and Re (wherein Rd and Re are the same or different, and are a hydrogen atom, hydroxy group, a C7-C13 aralkyloxy group, a C1-C6 alkyl group which is optionally substituted with a hydroxyl group, alternatively taken together with the adjacent nitrogen atom to form a monocyclic or bicyclic 4 to 10-membered saturated or unsaturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen, a sulfur and an oxygen atom, which may be substituted with an amino group, a spiro heterocyclic group, or a bridged heterocyclic group), or —S(═O)₂Rf (wherein Rf is an amino group, a C1-C6 alkyl group, or a 4 to 10-membered saturated heterocyclic group).

In the compounds represented by the formula (I), R³ is more preferably a C6-C10 aromatic hydrocarbon group, or a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ is optionally substituted with R³¹, and when it has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group consisting of the group selected from a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl groups; a C1-C14 acyl group; a C1-C14 acylamino group; a C1-C14 acyloxy group);

R³¹ is a halogen atom, a cyano group, a nitro group, a carboxyl group, thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group, a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), C6-C10 aromatic hydrocarbon group (which may be substituted with a halogen atom), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a C1-C6 alkyl group or an oxo group), —CONH₂ group, (mono- or di-C1-C6 alkyl) aminocarbonyl group, a hydroxyamino group, (C7-C13 aralkyl) oxy aminocarbonyl group, a cyclic amino carbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl group.

In the compounds represented by the formula (I), R³ is more preferably a C6-C10 aromatic hydrocarbon group (wherein the C6-C10 aromatic hydrocarbon group is optionally substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 4 to 6-membered saturated or partially unsaturated hetero ring having 1 to 3 hetero atoms (which is optionally substituted with a group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 5 to 6-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C2-C7 alkoxycarbonyl group, a —CONH₂ group (mono- or di-C1-C6 alkyl) aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group, a 3-oxa-8-azabicyclo[3.2.1]octanyl group, and an 8-oxa-3-azabicyclo[3.2.1]octanyl group);

R³¹ is a halogen atom, an amino group, a C1-C6 alkyl group (which is optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group), a C1-C6 alkoxy group (which is optionally substituted with a halogen atom), a 5 or 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono or di-C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino group.

Also, in the compounds represented by formula (I), R³ is particularly preferably a phenyl group (wherein the phenyl group may be substituted with R³¹, and when a phenyl group has two substituents on the carbon atoms which are adjacent each other on a benzene ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 6-membered saturated or partially unsaturated hetero ring having one or two oxygen atoms (which is optionally substituted with a group selected from the group consisting of a hydroxy group and a C1-C6 alkyl group)), or a pyridyl group (optionally substituted with a —CONH₂ group, a (mono or di C1-C6 alkyl) aminocarbonyl group, or a pyrrolidin-1-yl carbonyl group);

R³¹ is a halogen atom, an amino group, a C1-C6 alkoxy group, or a —CONH₂ group.

In the compounds represented by the formula (I), R⁴ is a hydrogen atom, or a C1-C6 alkyl group.

“C1-C6 alkyl group” indicated in R⁴ is preferably a C1-C3 alkyl group, more preferably a methyl group.

R⁴ is preferably a hydrogen atom, or a methyl group, more preferably a hydrogen atom.

In the compounds of formula (I) of present invention, preferred compounds include the following.

In formula (I),

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom;

X³ represents-NH—;

X⁴ represents a hydrogen atom or a methyl group;

R¹ represents —C(R¹¹)(R¹²) (wherein R¹¹ and R¹² are the same or different, and a hydrogen atom or C1-C6 alkyl group);

R² represents a C6-C14 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbons (which is optionally substituted with a C1-C6 alkyl group);

R²¹ is a halogen atom, a cyano group, C1-C6 alkyl group (which is optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (which is optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkoxy group), or a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group);

R³ is a C6-C10 aromatic hydrocarbon group, or a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ is optionally substituted with R³¹, and when R³ has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group consisting of the group selected from a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; and C1-C14 acyloxy group);

R³¹ is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group, a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), a C6-C10 aromatic hydrocarbon ring (optionally substituted with a halogen atom), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a C1-C6 alkyl group and an oxo group), —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group, a (C7-C13 aralkyloxy)oxyaminocarbonyl group, a cyclic aminocarbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl group; and

R⁴ represents a hydrogen atom;

or a salt thereof.

Furthermore, in the compounds of formula (I) of the present invention, more preferable compounds include the following.

In formula (I),

X¹ represents an oxygen atom;

X² represents an oxygen atom;

X³ represents-NH—;

X⁴ represents a hydrogen atom;

R¹ represents —C(R¹¹)(R¹²) (wherein R¹¹ represents a C1-C6 alkyl group, and R¹² represents a hydrogen atom);

R² represents a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbons (which is optionally substituted with a C1-C6 alkyl group);

R²¹ is a halogen atom, a C1-C6 alkyl group or a monocyclic 5 to 6-menbered unsaturated heterocyclic group having 1 to 3 nitrogen atom(s) (which is optionally substituted with a C1-C6 alkyl group);

R³ is a C6-C10 aromatic hydrocarbon group (wherein the C6-C10 aromatic hydrocarbon group is optionally substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 4 to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and C1-C14 acyloxy group) or a monocyclic 5 to 6-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C2-C7 alkoxycarbonyl group, a —CONH₂ group, (mono- or di-C1-C6 alkyl) aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group, a 3-oxa-8-azabicyclo[3.2.1]octanyl group, and an 8-oxa-3-azabicyclo[3.2.1]octanyl group);

R³¹ is a halogen atom, an amino group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a monocyclic 5 to 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, a —CONH₂ group, (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group; and

R⁴ represents a hydrogen atom;

or a salt thereof.

In the compounds of formula (I) of the present invention, more preferable compounds include the following.

In formula (I),

X¹ represents an oxygen atom;

X² represents an oxygen atom;

X³ represents-NH—;

X⁴ represents a hydrogen atom;

R¹ represents —C(R¹¹)(R¹²) (wherein R¹¹ represents a methyl group, and R¹² represents a hydrogen atom);

R² represents a phenyl group or a naphthyl group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbons (which is optionally substituted with a C1-C6 alkyl group);

R²¹ is a halogen atom or a C1-C6 alkyl group;

R³ is a phenyl group (wherein the phenyl group is optionally substituted with R³¹, and when a phenyl group has two substituents on the carbon atoms which are adjacent each other on a benzene ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 6-membered saturated or partially unsaturated heterocyclic ring having 1 or 2 oxygen atom(s) (optionally substituted with a group selected from the group consisting of a hydroxyl group and a C1-C6 alkyl group), or a pyridyl group (optionally substituted with a —CONH₂ group, a (mono- or di-C1-C6 alkyl) aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group)

R³¹ is a halogen atom, an amino group, a C1-C6 alkoxy group, a —CONH₂ group; and

R⁴ represents a hydrogen atom;

or a salt thereof.

Particularly preferable compounds of the present invention include the following.

-   (1)     5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (2)     5-chloro-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (3)     5-bromo-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (4)     5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (5)     5-chloro-2-(N-((1S,2R)-2-(2-fluoronaphtalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (6)     5-chloro-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (7)     5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (8)     5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide; -   (9)     2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chloro-benzamide; -   (10)     5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(pyrrolidine-1-carbonyl)pyridine-2-sulfonamide; -   (11)     5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide; -   (12)     5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-chroman-8-sulfonamide; -   (13)     N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methyl-chroman-8-sulfonamide; -   (14)     5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide; -   (15)     5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide; -   (16)     3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N,N-dimethylpicolinamide; -   (17)     4-amino-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide; -   (18)     4-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide;     and -   (19)     5-chloro-2-((1S,2R)-methyl-d3-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide.

A method of preparing the compound according to the present invention is described by giving examples. The compounds of the formula (I) of the present invention, for example, can be prepared by the following production method. However, the present invention is not limited to this method.

[wherein, L¹ represents a leaving group. The symbols have the same meanings as defined above.] [A-1]

In this process, a compound represented by general formula (4) can be prepared by reacting a compound represented by general formula (1) with an organometallic reagent (3) such as Grignard reagent represented by R¹¹MgHal.

Hal represents a halogen atom.

The amount of Grignard reagent (3) 0.8 to 20 equivalents relative to compound (1), preferably 1.0 to 10 equivalents. The reaction temperature is −80° C. to 100° C., preferably −78° C. to 50° C. The reaction time is 0.1 to 24 hours, preferably 0.1 to 3 hours.

In this step, a compound represented by general formula (4), wherein R¹¹ is H, can be prepared by reacting the compound represented by formula (1) with a well-known reducing agent instead of Grignard reagent (3).

The reducing agents to be used include, for example, sodium borohydride, lithium borohydride, lithium aluminum hydride, diethoxy aluminum lithium hydride, triethoxy lithium aluminum hydride, tri-t-butoxy aluminum lithium hydride, aluminum magnesium hydride, aluminum hydride magnesium chloride, sodium aluminum hydride, sodium triethoxyaluminum hydride, bis(2-methoxyethoxy) aluminum sodium hydride, diisobutylaluminum hydride (hereinafter DIBAL-H) and the like, and preferably sodium borohydride.

The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like), alcohols (methanol, ethanol, and the like), and water, and preferably methanol.

The amount of reducing agent used is 0.8 to 10 equivalents relative to the compound (1), preferably 1 to 5 equivalents.

The reaction temperature is from 0° C. to the boiling point temperature of the solvent, preferably 0 to 40° C. The reaction time is from 0.05 to 24 hours, preferably 0.2 to 2 hours. Thus, the compound represented by general formula (4) obtained in the above manner can be subjected to the next step with or without isolation and purification by a well-known separation and purification means described below

[A-2]

In this step, a compound represented by general formula (4) can be prepared by reacting a compound represented by general formula (2) with well-known reducing agents,

The reducing agents to be used include sodium borohydride.

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, and, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), alcohols (methanol, ethanol, 2-propanol, tert-butanol, ethylene glycol, etc.), water and the like, preferably methanol or ethanol.

The amount of reducing agent is 0.8 to 10 equivalents relative to the compound (2), preferably 1 to 5 equivalents.

The reaction temperature is between 0° C. and the boiling point temperature of the solvent, preferably 0 to 40° C. The reaction time is from 0.05 to 24 hours, preferably 0.2 to 2 hours. Thus, the obtained compound represented by general formula (4) can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

[A-3]

In this process, a compound represented by general formula (5) can be prepared by reacting a compound represented by general formula (4) with a halogenating agent or sulfonyl halide hydrocarbons.

Leaving groups represented by L¹ are, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group, an organic sulfonyloxy group such as a p-tolylsulfonyloxy group.

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.), aromatic hydrocarbons (benzene, toluene, xylene, pyridine, etc.), and preferably ethers.

The halogenating agents to be used are, for example, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl bromide, phosphorus tribromide and the like. Preferably, it is thionyl chloride or phosphorus tribromide. The sulfonyl halide hydrocarbons are, for example, methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride or phenylsulfonyl chloride and the like.

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, and, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), and preferably dichloromethane.

The amount of the halogenating agent or sulfonyl halide hydrocarbons is 0.3 equivalents to 20 equivalents relative to the compound (4), preferably 0.3 to 4 equivalents.

The reaction temperature is −20° C. to 100° C., preferably from 0° C. to 100° C. The reaction time is generally 0.01 to 200 hours, preferably 0.5 hour to 24 hours. Thus, the obtained compound represented by general formula (5) can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

[Symbols in the Formula are as Defined Above.] [B-1]

In this process, a nickel complex represented by general formula (7) is prepared by reacting a compound represented by general formula (1) or (5) with a readily available compound represented by formula (6).

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, and for example, organic solvents or mixtures thereof such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (N,N-dimethylformamide (hereinafter, also referred to as DMF), N,N-dimethylacetamide, N-methylpyrrolidinone, and preferably DMF.

The bases to be used are, for example: organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, or collidine; alkali metal salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; a strong base lithium amide such as lithium diisopropylamide; a strong base hexamethyldisilazane such as lithium hexamethyl disilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane; and preferably sodium hydroxide, potassium hydroxide, potassium tert-butoxide and the like.

The amount of the base to be used is usually 0.1 to 100 equivalents relative to compound (6), preferably 1 to 20 equivalents.

The amount of compound (1) or (5) is 0.5 to 10 equivalents relative to compound (6), preferably 1 to 5 equivalents.

The reaction temperature is −80 to 50° C., preferably −60 to 40° C. The reaction time is 0.2 to 24 hours, preferably 0.5 to 6 hours. The pressure used in the above preparing method may not be particularly limited, and examples thereof include, about 0.1 to 10 atm. A nickel complex represented by general formula (7) which is obtained in this method can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

[B-2]

In this step, an amino acid represented by general formula (8) can be prepared by reacting the nickel complex or a salt thereof with an acid represented by general formula (7).

The acids to be used are not particularly limited but include publicly known acids. The acids may be an inorganic acid or an organic acid. The inorganic acids include such as hydrochloric acid, nitric acid, sulfuric acid, and perchloric acid. The organic acids include such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, oxalic acid, propionic acid, butyric acid, valeric acid, and the like. Preferably, the acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid, or methanesulfonic acid, more preferably, it is hydrochloric acid, or methanesulfonic acid.

The amount of the acid is not particularly limited, and usually 0.1 to 50 equivalents relative to the nickel complex represented by general formula (7), and preferably 0.3 to 10 equivalents.

The solvent to be used is preferably alcohol, more preferable to methanol or ethanol.

The reaction temperature is usually 0° C. to 100° C., and preferably 40 to 80° C. The reaction time is usually 0.1 to 72 hours, and preferably 0.1 to 10 hours. The pressure used in the above preparing method is not particularly limited, and examples thereof include, 0.1 to 10 atm. The amino acid represented by general formula (8) obtained in the present method can be subjected to the next process with or without a separation and purification means by well-known separation and purification means described below or transformation between protection and deprotection.

[Symbols in the Formula are as Defined Above.]

[C-1]

In this step, a compound represented by general formula (10) can be prepared by reacting a compound represented by general formula (9) with a well-known reducing agent.

The reducing agent is tri(ethoxy) aluminum lithium hydride, tri(sec-butyl)boron lithium hydride, or DIBAL-H, and the like, and preferably DIBAL-H.

The amount of the reducing agent is usually 1 to 10 equivalents relative to the compound (9), preferably 2.0 to 10 equivalents.

The solvent to be used is ether type solvents (tetrahydrofuran, 1,4-dioxane, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.), halogen solvents (dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents (toluene, xylene, etc.) or a mixed solvent thereof and the like, and preferably dichloromethane.

The reaction temperature is −100° C. to 50° C., preferably −100 to 10° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 5 hours.

The pressure used in the above preparing method may not be particularly limited, and examples thereof include, from about 0.1 to 10 atm.

The compound represented by general formula (10) which is the obtained in this method can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

The compound represented by general formula (9) can be prepared by the methods described in the reference (international publication No. WO2011/071,565), or, if necessary, combining the methods described in the reference examples and examples.

[C-2]

In this step, a compound represented by general formula (11) is prepared by reacting with a compound represented by general formula (10) with a cyanide agent and ammonia. The cyanide agent to be used is, for example, hydrogen cyanide, metal cyanides, cyanohydrin compounds, acyl cyanides, halogenated cyanides and the like. The metal cyanides are, for example, alkali metal cyanides such as sodium cyanides, potassium cyanides; alkaline earth metal cyanides such as calcium cyanide; transition metal cyanides such as copper cyanide. Preferably, it is potassium cyanide.

The ammonia used in in the present step can be ammonia gas, liquid ammonia or an aqueous ammonia solution, and an aqueous ammonia solution is desirable in terms of that it does not require complicated reaction apparatus.

The solvent to be used is not particularly limited as long as it does not affect the reaction, and it includes ethers (tetrahydrofuran, 1,4-dioxane, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxides, acetonitrile, etc.), halogen solvents (dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents such as toluene, alcohol solvents (methanol, ethanol, etc.), water, and a mixed solvent thereof, and preferably water and a mixed solvent of methanol.

The amount of cyanide agent to be used is generally 1 to 10 equivalents relative to compound (10), preferably 2.0 to 5.0 equivalents. The amount of ammonia used in the reaction is preferably 1.5 to 10 equivalents relative to the compound (10), and more preferably 1.8 to 2.5 equivalents. Ammonium chloride is added as needed. Its amount is usually 0.2 to 2.0 equivalents relative to the compound of (10), preferably 0.1 to 0.5 equivalent.

The reaction temperature is −100° C. to 100° C., preferably 0 to 60° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 5 hours. The pressure used in the above preparing method may not be particularly limited, and examples thereof include, from about 0.1 to 10 atm. The compound represented by general formula (11) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[C-3]

In this process, the compound represented by general formula (12) is prepared in the same manner as [B-2] described above using the compound represented by general formula (11). The compound represented by general formula (12) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below. Hereinafter, post process for the compounds represented by general formulae (8) and (12) are described as an example.

Furthermore, in the present process, R¹ and R² can be converted to the structures corresponding to protection/deprotection groups or the present invention.

[In the formula, L² represents a leaving group. The symbols have the same meanings as defined above.]

[D-1]

In this step, a carboxylic acid represented by general formula (14) can be prepared by reacting an amino acid represented by general formula (12) with a sulfonic acid halide represented by general formula (13) in the presence of a base.

The base to be used is alkali metal salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, or organic amines such as trimethylamine or potassium hydroxide, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, and collidine are exemplified, and preferably triethylamine.

The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and it is organic solvents or water, etc. such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. These solvents may be used in a mixture at an appropriate ratio.

The number of equivalents of base and an amine is from 0.5 to 10 equivalents, respectively, preferably 1.0 to 5.0 equivalents.

The amount of the sulfonic acid halide is appropriately set by the compounds represented by general formula (12), but is not limited to, and usually, is 1.0 to 5.0 equivalents relative to the compound represented by general formula (12), more preferably 1.0 to 2.5 equivalents.

The reaction temperature is appropriately by the compounds represented by general formula (12), but is not limited to, and, for example, a −20 to 70° C., preferably 0 to 40° C. The reaction time is generally 0.1 to 24 hours, preferably 0.2 to 6.0 hours. The compound represented by general formula (14) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The compound represented by general formula (13) can be prepared by the methods described in the reference (Tetrahedoron Lett. 51, 418-421 (2010)), or, if necessary, combining the methods described in the reference examples and examples.

[D-2]

In this step, a compound represented by general formula (15) can be prepared by reacting a carboxylic acid represented by general formula (14) with a condensing agent and hydrazine. Alternatively, it can be prepared by reacting hydrazine derivative having an appropriate protecting group with the carboxylic acid represented by general formula (14) in the same manner, and then carrying out the reaction for eliminating the protecting group.

The condensing agent is, for example 1,1′-carbonyldiimidazole (hereinafter, CDI), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, preferably CDI.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), and amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, and they can be used alone or in combination.

The amount of the condensing agent with respect to the compound represented by Formula (14) is generally 1 to 50 equivalents, preferably about 1 to 5. The amount of hydrazine relative to the compound represented by general formula (14) is generally 1 to 100 equivalents, preferably 1-5 equivalents. The base is organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The reaction temperature is −20 to 80° C., preferably 0 to 40° C. The reaction time is usually from 0.05 to 24 hours, more preferably 0.05 to 6 hours. The compound represented by general formula (15) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[D-3]

In this step, a compound represented by general formula (16) of the present invention can be prepared by cyclization of the compound represented by general formula (15) with the acylating agent.

The acylating agent is, for example isobutyl chloroformate, CDI, phosgene, triphosgene and the like, preferably CDI. The base is, organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and like diazabicycloundecene and the like.

The amount of the acylating agent with respect to the compound represented by Formula (15) is typically preferably 1 to 50 equivalents, and more preferably 1 to 5 equivalents.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, etc.) and the like, and they may be used singly or as a mixture.

The reaction temperature is −20 to 80° C., preferably 0 to 50° C. The reaction time is generally 0.5 to 24 hours, preferably 0.5 to 8 hours. The compound represented by general formula (16) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The compound represented by general formula (16) of the present invention can be synthesized by 1) protecting the amino group of the amino acid of the compound represented by above general formula (12) with a well-known suitable protecting group, 2) converting the carboxylic acid moiety to the oxadiazolone ring in the same method as [D-2], 3) deprotecting the protective group in a well-known method, 4) sulfonamidation in the same manner as [D-1].

[In the formula, the symbols have the same meanings as defined above.]

[E-1]

In this step, a compound represented by general formula (17) of the present invention can be prepared by reacting the compound represented by general formula (15) with carbon disulfide.

The base used in this reaction is, for example, alkali metal salts such as sodium hydroxide, potassium hydroxide, organic amines such as triethylamine, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal amides such as lithium diisopropylamide, and preferably potassium hydroxide.

The amount of the base to be used is, with respect to the compound represented by Formula (15), generally 1 to 20 equivalents, preferably 1 to 5 equivalents. The amount of carbon disulfide is, with respect to the compound represented by Formula (15), generally 1 to 20 equivalents, preferably 1 to 5 equivalents.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents, water such as alcohols (methanol, ethanol, propanol), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, and the like, and they can be used singly or as a mixture.

The reaction temperature is 0 to 150° C., preferably between 20 to 100° C. The reaction time is generally from 0.5 to 24 hours, preferably 1.0 to 12 hours. The compound represented by general formula (17) of the present invention can be isolated and purified by well-known separation and purification means.

[In the formula, the symbols have the same meanings as defined above.]

[F-1]

In this step, a compound of general formula (18) can be prepared by condensation and simultaneously cyclization of the compound represented by general formula (1 4) and thiosemicarbazide.

The condensing agent is, for example CDI, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. They may be used singly or as a mixture.

The amount of the condensing agent is, with respect to the compound represented by general formula (14), 1.0 to 50 equivalents, preferably 1 to 5 equivalents. The amount of thiosemicarbazide is, with respect to the compound represented by general formula (14), generally 1 to 100 equivalents, preferably 1.0 to 5.0 equivalents. The base is organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The reaction temperature is −20 to 180° C., preferably 0 to 100° C. The reaction time is usually 0.05 to 24 hours, preferably 0.05 to 6 hours. The compound represented by formula (18) of the present invention can be isolated and purified by well-known separation and purification means as described below.

[In the formula, the symbols have the same meanings as defined above.]

[G-1]

In this step, a compound represented by general formula (19) can be prepared by reacting the carboxylic acid represented by general formula (14) with a condensation agent and ammonia.

The condensing agent is, for example, 1,1′-carbonyldiimidazole (hereinafter, CDI), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, preferably CDI.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. They may be used singly or as a mixture.

The amount of the condensing agent with respect to the compound represented by general formula (14) is generally 1 to 50 equivalents, preferably 1 to 5 equivalents. Ammonia is used as an aqueous solution or hydrochloric acid salt, and its amount relative to the compound represented by general formula (14) is generally 1 to 100 equivalents, preferably 1.0 to 5.0 equivalents. The bases include, for example, organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The reaction temperature is −20 to 80° C., preferably 0 to 40° C. The reaction time is usually from 0.05 to 24 hours, preferably 0.05 to 6 hours. The compound represented by general formula (19) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[G-2]

In this step, a nitrile represented by general formula (20) can be prepared from the amide compound represented by general formula (19).

Dehydrating agents include, for example, oxalyl chloride, thionyl chloride, cyanuric chloride and the like, preferably cyanuric chloride.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. They may be used singly or as a mixture.

The amount of dehydrating agent with respect to the compound represented by general formula (19) is usually 1 to 50 equivalents.

The reaction temperature is −20 to 80° C., preferably between 0 to 40° C. The reaction time is usually from 0.05 to 24 hours, preferably from 0.05 to 3 hours. The compound represented by general formula (20) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[G-3]

In this step, an amidoxime compound is obtained from the nitrile compound represented by general formula (20) by adding hydroxylamine, and then it reacts with an acylating agent followed by cyclization reaction with application of heat to produce a compound represented by general formula (21).

The amount of the hydroxylamine to be used for preparing amidoxime is generally 1 to 50 equivalents in reaction to the compound represented by general formula (20).

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvent such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like). They may be used singly or as a mixture.

The reaction temperature is −20 to 100° C., preferably 0 to 60° C. The reaction time is generally from 0.05 to 3 days, preferably 0.05 to 12 hours. The obtained amidoxime compound represented by general formula (20) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The acylating agent used for amide oxime is, for example, chloroformate, 2-ethylhexyl, CDI, phosgene, triphosgene and the like, preferably chloroformate 2-ethylhexyl. The base to be used includes organic bases such triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The amount of the acylating agent is usually 1 to 50 equivalents relative to the amide oxime compound, and more preferably about 1 to 3 equivalents.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, etc.) and the like), and they can be used singly or as a mixture, and they can be switched to other solvents during the reaction.

The reaction temperature with the acylating agent is to −20, 80° C., preferably 0 to 40° C. The reaction time is generally 0.5 to 24 hours, preferably 0.5 to 3 hours. The reaction temperature used for cyclization reaction of the obtained acylated compound is 0 to 150° C., preferably 0 to 120° C. The reaction time is generally from 0.5 to 24 hours, preferably 0.5 to 12 hours. The obtained compound represented by general formula (21) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The compound represented by formula (I) of the present invention and intermediates thereof can be isolated and purified by well-known separation and purification means such as recrystallization, crystallization, distillation, or column chromatography. The compound of the present invention and synthetic intermediates are usually possible to form a pharmacologically acceptable salt thereof in a well-known manner, and also can be converted to each other.

When optical isomers, stereoisomers, tautomers, or rotary isomers are present in the compound of the present invention, the compound of the present invention encompasses these isomers or the mixture thereof. For example, when an optical isomer in the compound of the present invention is present, unless otherwise stated, racemate and an optical isomer resolved from a racemate are also encompassed in the compound of the present invention. These isomers can be obtained by a well-known synthetic method, separation means (concentration, solvent extraction, column chromatography, recrystallization and the like) respectively with a single compound. In the compound of the present invention, for example, when X¹=oxygen atom, X²=oxygen atom, X³═NH, there are tautomers as shown below, any of the isomers are also included in the present invention.

The compound of the present invention or a salt thereof may be amorphous (amorphous) or a crystalline form, and the crystalline form may be a single crystalline form or polymorphic mixture, which are encompassed by the compound of the present invention or a salt thereof. The crystals can be prepared by applying a well-known crystallization method.

Furthermore, the compound of the present invention or a salt thereof can be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound of the present invention or a salt thereof. The compounds labeled with isotopes (e.g., deuterium, ³H, ¹⁴C, ³⁵S, ¹²⁵I, etc.) and the like are also encompassed by the compound of the present invention or a salt thereof.

Although the prodrugs of the compound of the present invention or a salt thereof are also included in the present invention, the prodrugs refer to the compounds which convert into the compound of the present invention or a salt thereof by a reaction with an enzyme or gastric acid under the physiological condition in the living body, i.e., the compounds which convert into the compound of the present invention or a salt thereof by enzymatic oxidation, reduced, or hydrolysis and the like or the compounds which convert into the compound of the present invention or a salt thereof by gastric acid. Furthermore, a prodrug of the compound of the present invention or a salt thereof may be the compounds which convert into the compound of the present invention or a salt thereof under physiological conditions as described in Hirokawa Shoten 1990 annual “Development of Pharmaceuticals” Volume 7 Molecular Design pages 163-198.

A salt of the compound of the present invention means a salt that is pharmaceutically acceptable.

The compound of the present invention or a salt thereof has an inhibitory activity against RNR. The compound of the present invention or a salt thereof is useful as a medicament for prevention or treatment of RNR-related diseases without causing side effects based on the off-target effects of the iron ions requiring protein due to its excellent RNR inhibitory activity and its structure that does not chelate to metal ions. The “RNR-related disease” includes diseases whose incidence can be decreased or whose symptom is in remission or alleviated and/or completely cured by deleting or suppressing and/or inhibiting functions of RNR. Such diseases are, for example, malignant tumors. Malignant tumors of interest is not particularly limited, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder⋅bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumor and the like.

“RNR” herein includes a human or non-human RNR, preferably a human RNR.

Accordingly, the present invention provides an RNR inhibitor including the compound of the present invention or a salt thereof as an active ingredient. Furthermore, the present invention relates to the use of the compound of the present invention or a salt thereof for the manufacture of the RNR inhibitors. The present invention also provides the use of the compound of the present invention or a salt thereof as RNR inhibitors. Furthermore, the present invention provides the compound of the present invention or a salt thereof for use as RNR inhibitors.

In yet another embodiment, the present invention provides a medicament containing the compound of the present invention or a salt thereof as an active ingredient. Furthermore, the present invention relates to use of the compound of the present invention or a salt thereof for the manufacture of a medicament. Further, the present invention provides the use as medicaments of the compound of the present invention or a salt thereof. Further, the present invention provides the compound of the present invention or a salt thereof for use as a medicament.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a salt thereof and a pharmaceutically acceptable carrier.

In a preferred embodiment, the medicament or pharmaceutical composition is a therapeutic agent for the RNR-related diseases, in a more preferred embodiment, the medicament or pharmaceutical composition is an antitumor agent.

In yet another embodiment, the present invention comprises administering an effective amount of the compound of the present invention or a salt thereof to a subject to provide an RNR activity suppression method. Further, the present invention comprises administering an effective amount of the compound of the present invention or a salt thereof to a subject to provide a method of treating RNR-related diseases. In a preferred embodiment, a method of treating RNR-related diseases is a method of treating tumors. In the treatment method, the subjects include human or non-human animal in need of the method.

When using the compound of the present invention or a salt thereof as a pharmaceutical, it is optionally formulated with a pharmaceutically acceptable carrier, and various dosage forms can be adopted depending on the prevention or therapeutic purposes, and as the dosage forms include, for example, oral agents, injections, suppositories, ointments, and any of such patches. Since the compound of the present invention or a salt thereof has an excellent oral absorbability, oral agents are preferable. These dosage forms can be prepared by preparation methods commonly known by a person with ordinary skill in the art.

With respect to pharmaceutically acceptable carriers, conventional various organic or inorganic carrier substances are used as pharmaceutical materials, and it is formulated as: excipients, binders, disintegrating agents, lubricants, coloring agents for solid preparations; and solvents, solubilizing agents, suspending agents, isotonizing agents, buffers, soothing agent for liquid preparations and the like. Further, if necessary, pharmaceutical additives can also be used, which include such as preservative agents, antioxidants, coloring agents, sweetening agents, flavoring agents, stabilizing agents.

With respect to the pharmaceutically acceptable carriers and the pharmaceutical additives, in general, they include, for example, as the excipient, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like; as are binders, water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, and the like; as disintegrants, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like; as lubricants, purified talc stearate, borax, polyethylene glycol and the like; as colorant, titanium oxide, iron oxide and the like; as flavoring agents, sucrose, orange peel, citric acid, tartaric acid and the like.

When preparing an oral solid preparation, it can be prepared by adding an excipient to the compound of the present invention, and if necessary, further adding binders, disintegrants, lubricants, colorants, or flavoring agents and the like, followed by formulating into tablets, coated tablets, granules, powders, capsules and the like.

When preparing injectable forms, it can be prepared by adding pH control agents, buffers, stabilizers, isotonic agents, local anesthetic agents and the like to the compound of the present invention, followed by formulating into subcutaneous, intramuscular and intravenous injections with a conventional manner.

The amount of the compound of the present invention to be formulated in each dosage unit forms described above can be, in general, per dosage unit form, 0.05 to 1000 mg for the oral dosage, about 0.01 to 500 mg for injection, 1 to 1000 mg for suppositories with the proviso that they may be altered depending on the symptoms of the patients to be applied or its dosage forms.

Further, the daily dose of a drug with the dosage form is, with respect to the compound of the present invention, 0.05 to 5000 mg per day for adult (body weight 50 kg), preferably 0.1 to 2000 mg, and preferably the aforementioned amount is administered once or 2 to 3 times a day with the proviso that they may be altered depending on symptoms of the patients, weight, age, or gender and the like.

EXAMPLES

The present invention is described below in more detail with examples and test examples, but the present invention is not intended to be limited to these examples.

Various reagents used in the examples were commercially available products, unless otherwise stated. Biotage Ltd. SNAP-ULTRA (registered trademark) Silica prepacked column was used for a silica gel column chromatography, or Biotage made SNAP KP-C18-HS (registered trademark) Silica prepacked column was used for a reverse phase silica gel column chromatography. HPLC purified by preparative reverse phase column chromatography was performed under the following conditions. Injection volume and gradient was carried out appropriately.

Column: YMC-Actus Triart C18, 30×50 mm, 5 μm

UV detection: 254 nm

Column flow rate: 40 mL/min

Mobile phase: water/acetonitrile (0.1% formic acid)

Injection amount: 1.0 mL

Gradient: water/acetonitrile (10% to 90%)

AL400 (400 MHz; JEOL (JEOL)) and Mercury400 (400 MHz; Agilent Technologies) were used for NMR spectra, and tetramethylsilane was used as an internal standard when tetramethylsilane was included in the heavy solvent, otherwise it was measured using NMR solvent as an internal standard, showing all 6 value in ppm. Furthermore, LCMS spectra were measured under the following conditions using a Waters made ACQUITY SQD (quadrupole).

Column: Waters made ACQUITY UPLC (registered trademark) BEH C18, 2.1×50 mm, 1.7 μm

MS detection: ESI negative

UV detection: 254 and 280 nm

Column flow rate: 0.5 mL/min

Mobile phase: water/acetonitrile (0.1% formic acid)

Injection amount: 1 μL

TABLE 1 Gradient Time (min) Water Acetonitrile 0 95 5 0.1 95 5 2.1  5 95 3.0 STOP The meanings of the abbreviations are shown below. s: singlet d: doublet t: triplet q: quartet dd: double doublet dt: double triplet td: triple doublet tt: triple triplet ddd: double double doublet ddt: double double triplet dtd: double triple doublet tdd: triple-double doublet m: multiplet br: broad brs: broad singlet DMSO-d₆: deuterated dimethyl sulfoxide CDCl₃: heavy chloroform CD₃OD: heavy methanol CDI: 1,1′-carboxymethyl sulfonyl diimidazole DAST: N,N-diethylaminosulfur trifluoride DIBAL-H: diisobutylaluminum hydride DMF: dimethylformamide DMSO: dimethylsulfoxide THF: Tetrahydrofuran WSC=EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt=1-hydroxybenzotriazole

Reference Example A1 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene

(Step 1) 1-(6-fluoro-2,3-dimethylphenyl)ethanol

After dropping a diethyl ether solution of methylmagnesium bromide (3.0 M, 70 mL) to a THF solution of 6-fluoro-2,3-dimethyl-benzaldehyde (22.0 g) (300 mL) at 0° C., the reaction mixture was stirred at room temperature for 1 hour. Under ice-bath condition, a saturated aqueous ammonium chloride solution (150 mL) was added dropwise, and ethyl acetate (200 mL) was added, and the resultant was separated into different layers. The organic layer was successively washed with HCl (1M, 200 mL), water (200 mL) and saline (200 mL), and then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1-(6-fluoro-2,3 dimethylphenyl)ethanol (23.7 g).

Step 2

Phosphorus tribromide (26.5 mL) was added dropwise at 0° C. to a chloroform solution (120 mL) of 1-(6-fluoro-2,3-dimethylphenyl)ethanol (23.7 g) obtained in the above Step 1, and the reaction solution was stirred for 30 minutes at 0° C. The reaction mixture was added to an ice-cold saturated aqueous sodium bicarbonate (1 L). After chloroform (500 mL) was added to the mixture, the resultant was separated into different layers, and the organic layer was successively washed with water (200 mL) and saline (200 mL). The organic layer was dried over anhydrous magnesium sulfate to give the title compound (29.5 g) by concentrating under reduced pressure.

Reference Example A2 to A41

Aldehyde and methylmagnesium bromide were reacted together as starting materials in the same manner as in Reference Example A1, Step 1 and Step 2, and then the resultant was reacted with phosphorus tribromide to obtain the compounds of Reference Examples A2 to A41. However, the compounds of Reference Examples A40 and A41 were obtained in the same procedure using ethylmagnesium bromide and methyl iodide-d3-magnesium respectively instead of methylmagnesium bromide.

TABLE 1-1 Reference Synthesized Example Starting Material Compound A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

TABLE 1-2 Reference Synthesized Example Starting Material Compound A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

TABLE 1-3 Reference Synthesized Example Starting Material Compound A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

Reference Example B1 2-(1-bromoethyl)-4-ethyl-1-fluoro-3-methylbenzene

(Step 1) 2-bromo-3-ethyl-6-fluorobenzaldehyde

To a THF solution (150 mL) of 2-bromo-1-ethyl-4-fluorobenzene (14.4 g), a THF solution of lithium diisopropylamide (1.5 M, 54 mL) was added dropwise at −78° C. After stirring the reaction solution for 30 minutes, DMF (6.5 mL) was added and the mixture was further stirred for 20 minutes. Water (50 mL) and hydrochloric acid (6 M, 50 mL) were successively added dropwise to the reaction solution, and the mixture was extracted twice with hexane (100 mL). The combined organic layer was washed with saturated saline (50 mL) twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 2-bromo-3-ethyl-6-fluorobenzaldehyde (14.5 g) was obtained.

(Step 2) 3-ethyl-6-fluoro-2-methylbenzaldehyde

To a 1,4-dioxane solution (200 mL) of 2-bromo-3-ethyl-6-fluorobenzaldehyde obtained from Step 1 above (14.5 g), water (90 mL), tripotassium phosphate (32.0 g), methylboronic acid (6.4 g) and [bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane additive (1.75 g) were added, and the reaction solution was heated under reflux at 110° C. for 2 hours. The reaction solution was allowed to cool to room temperature, and the mixture was further stirred for 2 hours after hexane (90 mL) was added. The reaction solution was filtered through CELITE, and the filtrate was separated after the residue was washed with hexane. The organic layer was washed twice with saturated saline (100 mL), and after being dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate), and 3-ethyl-6-fluoro-2-methylbenzaldehyde (8.4 g) was obtained.

Step 3

According to the methods of Reference Example A1 Steps 1 and 2, using 3-ethyl-6-fluoro-2-methylbenzaldehyde (8.4 g) obtained in the above Step 2, the same operation was carried out to obtain the title compound.

Reference Examples B2 to B6

According to the methods of Reference Example B1 Steps 1 and 2 and Reference Example A1 Steps 1 and 2, the following compounds of Reference Examples B2 to B5 were synthesized. Also, according to the methods of Reference Example B1 Step 1, and Reference Example A1 Steps 1 and 2, the compound of Reference Example B6 was synthesized.

TABLE 2 Reference Synthesized Example Starting Material Compound B2

B3

B4

B5

B6

Reference Example C1 7-(l-chloroethyl)-1-methyl-2,3-dihydro-1H-indene

Sodium borohydride (261 mg) was added to a methanol solution (5.0 mL) of 1-(3-methyl-2,3-dihydro-1H-inden-4-yl)ethanone (1.0 g), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was added to water (10 mL) and then extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5.0 mL), thionyl chloride (2.0 mL) was added at room temperature, and the reaction solution was stirred at 50° C. for 30 minutes. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.1 g).

Reference Examples C2 to C4

According to the method of Reference Example C1, the following compounds of Reference Examples C2 to C4 were synthesized.

TABLE 3 Reference Synthesized Example Starting Material Compound C2

C3

C4

Reference Example D1 (2S, 3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic Acid

A DMF solution (50 mL) of 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (14.0 g) obtained in Reference Example A1 was added dropwise to a DMF solution (50 mL) of (S)-2-[o-[(N-benzylprolyl)amino]phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II) (14.5 g), and potassium hydroxide (16.3 g), and the mixture was stirred at the same temperature for 1 hour. A saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layers were washed successively with water (50 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane). The obtained compound was dissolved in methanol (120 mL), hydrochloric acid (3 M, 90 mL) was added, and the mixture was stirred at 80° C. for 45 minutes. Methanol was distilled off under reduced pressure, and chloroform (50 mL) and water (50 mL) were added to the residue. The aqueous layer was washed with chloroform (50 m L) and concentrated under reduced pressure. The residue was purified by reverse phase silica gel column chromatography (methanol/water) to give the title compound (2.0 g). ¹H NMR (CD₃OD) δ: 7.03 (dd, J=8.2, 5.7 Hz, 1H), 6.79 (dd, J=11.7, 8.4 Hz, 1H), 3.74-3.87 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.40 (dd, J=6.8, 2.4 Hz, 3H)

Reference Examples D2 to D58

After the alkylating agent obtained in Reference Examples A2 to A41, Reference Examples B1 to B6, and Reference Examples C1 to C4 and (S)-2-[o-[(N-benzylprolyl)amino]phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II) were reacted, the compounds of Reference Examples D2 to D58 shown below were prepared by acid hydrolysis. However, for the compound of Reference Example D56, 6-fluoro-2,3-dimethylbenzaldehyde was used as a starting material, and the compounds of Reference Examples D57 and 58 were prepared by the same method by using (R)-2-[o-[(N-benzylprolyl)amino] phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II) instead of (S)-2-[o-[(N-benzylprolyl)amino]phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II).

TABLE 4-1 Starting Material (Reference example number or Reference structural Example formula) Synthesized Compound D2 A1

D3 A2

D4 A3

D5 A4

D6 A5

D7 A6

D8 A7

D9 A8

D10 A9

D11 A10

D12 A11

D13 A12

TABLE 4-2 Starting Material (Reference example number or Reference structural Example formula) Synthesized Compound D14 A13

D15 A14

D16 A15

D17 A16

D18 A16

D19 A17

D20 A18

D21 A19

D22 A20

D23 A21

D24 A22

D25 A23

TABLE 4-3 Starting Material (Reference example number or Reference structural Example formula) Synthesized Compound D26 A24

D27 A25

D28 A26

D29 A27

D30 A28

D31 A29

D32 A30

D33 A31

D34 A32

D35 A33

D36 A33

D37 A34

TABLE 4-4 Starting Material (Reference example number or Reference structural Example formula) Synthesized Compound D38 A35

D39 A36

D40 A37

D41 A38

D42 A39

D43 A40

D44 A41

D45 B1

D46 B2

D47 B3

D48 B4

D49 B5

D50 B6

D51 C1

TABLE 4-5 Starting Material (Reference example number or Reference structural Example formula) Synthesized Compound D52 C1

D53 C2

D54 C3

D55 C4

D56

D57 A1

D58 A1

Reference Example D59 2-Amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanoic Acid Monohydrochloride

(Step 1) 2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanal

2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanenitrile (700 mg) was dissolved in dichloromethane (35 mL) and cooled to −78° C. A toluene solution (1.0 M, 10 mL) of diisobutylaluminum hydride was added, and the reaction solution was stirred for 1 hour at the same temperature. Methanol (5.0 mL) and CELITE (20 g) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through CELITE, washed with hexane/ethyl acetate=1/1 (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hexane/ethyl acetate) to obtain 2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanal (400 mg).

(Step 2) 2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanonitrile

2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanal (400 mg) obtained in the above Step 1 was dissolved in methanol (7.0 mL) and water (10 ml), 28% aqueous ammonia (280 μL), potassium cyanide (130 mg), and ammonium chloride (110 mg) were added, and the reaction solution was stirred for 12 hours at 70° C. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanonitrile (380 mg).

Step 3

2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanonitrile (380 mg) obtained from the above Step 2 was dissolved in hydrochloric acid (12M, 5.0 mL), and the reaction solution was stirred for 12 hours at 100° C. The reaction solution was cooled to room temperature and was concentrated under reduced pressure to obtain the title compound (300 mg).

Reference Example D60 2-Amino-2-(1-(6-fluoro-2,3-dimethylphenyl)cyclopropyl)acetic Acid Monohydrochloride

The title compound was synthesized according to the method of Reference Example D59, using 1-(6-fluoro-2,3-dimethylphenyl)cyclopropanecarbonitrile instead of 2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanenitrile.

Reference Example D61 2-Amino-3-(6-fluoro-2,3-dimethylphenyl)-3-butenoic Acid Monohydrochloride

(Step 1) 2-(6-fluoro-2,3-dimethyl)-2-hydroxy-propanenitrile

In dichloromethane (20 mL) solution of 1-(6-fluoro-2,3-dimethylphenyl)ethanone (1.3 g), zinc iodide (480 mg) and trimethylsilyl cyanide (2.0 mL) were added, and the reaction mixture was stirred for 12 hours at room temperature. An aqueous solution of sodium hydroxide (2 M, 10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (20 mL). The organic layer was washed with hydrochloric acid (2 M, 20 mL) and saturated saline (20 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-(6-fluoro-2,3-dimethyl)-2-hydroxy-propanenitrile (1.4 g).

(Step 2) 2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)propanenitrile

To dichloromethane solution (5.0 mL) of 2-(6-fluoro-2,3-dimethyl)-2-hydroxy-propanenitrile (170 mg) obtained from the above Step 1, DAST (150 μL) was added, and the reaction solution was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)propanenitrile (100 mg).

(Step 3) 2-amino-3-fluoro-3-(6-fluoro-2,3-dimethylphenyl)-butanenitrile

From 2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)propanenitrile obtained in the above Step 2, according to the method of Reference Example D59 Steps 1-2, 2-amino-3-fluoro-3-(6-fluoro-2,3-dimethylphenyl)-butanenitrile was obtained.

(Step 4) 2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-butenoic Acid Monohydrochloride

2-Amino-3-fluoro-3-(6-fluoro-2,3-dimethylphenyl)-butanenitrile (460 mg) obtained in the above Step 3 was dissolved in hydrochloric acid (12 M, 3.0 mL), and the mixture was stirred for 12 hours at 100° C. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the title compound.

Reference Example E1 5-chloro-8-(chlorosulfonyl)-4-methyl-d3-chroman-4-yl Acetate

(Step 1) 8-bromo-5-chloro-4-methylchroman-4-ol

THF (50 mL) was added to a diethyl ethyl ether solution (1.0 M, 63 mL) of methyl iodide-d3-magnesium, and a THF solution (50 mL) of 8-bromo-5-chlorochroman-4-one (7.5 g) was added dropwise at room temperature. The reaction solution was stirred for 10 minutes at the same temperature, in an ice bath, hydrochloric acid (1M, 50 mL) was slowly added dropwise, and ethyl acetate (50 mL) was added to separate layers. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layer was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-methylchroman-4-ol (7.7 g).

(Step 2) 8-bromo-5-chloro-4-methyl-d3-chroman-4-yl acetate

To an anhydrous acetic acid solution (100 mL) of 8-bromo-5-chloro-4-methylchroman-4-ol (7.7 g) obtained in the above Step 1, an acetonitrile solution (12 mL) of scandium trifluoromethanesulfonate (111) (340 mg) was added dropwise at −40° C., and the reaction solution was stirred for 30 minutes at the same temperature. A saturated aqueous sodium hydrogen carbonate solution (100 mL) and ethyl acetate (100 mL) were sequentially added to the reaction solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layers were washed twice with a saturated aqueous sodium hydrogen carbonate solution (100 mL) and once with saturated saline (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-methyl-d3-chroman-4-yl acetate (8.9 g).

(Step 3) 8-(benzylthio)-5-chloro-4-methyl-d3-chroman-4-yl acetate

To a 1,4-dioxane solution (70 mL) of 8-bromo-5-chloro-4-methyl-d3-chroman-4-yl acetate (6.7 g) obtained in the above Step 2, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (600 mg), tris(dibenzylideneacetone) dipalladium (0) (480 mg), N,N-diisopropylethylamine (7.2 mL) and benzylmercaptan (2.8 ml) were added, and the reaction solution was stirred for 2 hours at 90° C. The reaction solution was allowed to cool to room temperature and filtered through CELITE. After washing the residue with hexane (50 mL), water (50 mL) was added to the filtrate for layering. The organic layer was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-(Benzylthio)-5-chloro-4-methyl-d3-chroman-4-yl acetate (6.3 g).

Step 4

To an acetonitrile solution (100 mL) of 8-(benzylthio)-5-chloro-4-methyl-d3-chroman-4-yl acetate (6.3 g) obtained in the above Step 3, water (3 mL), acetic acid (4.3 mL) and 1,3-dichloro-5,5-dimethylhydantoin (7.2 g) were each added, and the reaction solution was stirred for 30 minutes at the same temperature. A saturated aqueous sodium hydrogen carbonate solution (70 mL) and ethyl acetate (70 mL) were added to the reaction solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate (70 mL). The combined organic layer was washed with saturated saline (70 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (5.3 g).

Reference Example E5 5-chloro-8-(chlorosulfonyl)-4-(trifluoromethyl)chroman-4-yl Acetate

(Step 1) 8-bromo-5-chloro-4-(trifluoromethyl)chroman-4-ol

To a THF solution (4 mL) of 8-bromo-5-chloro-chromanon-4-one (398.2 mg), cesium fluoride (340.2 mg) and trifluoromethyltrimethylsilane (0.68 mL) were added at room temperature, and the reaction solution was stirred for 4 hours. An ammonium chloride aqueous solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-(trifluoromethyl)chromanone-4-ol (139.2 mg).

Step 2

From 8-bromo-5-chloro-4-(trifluoromethyl)chroman-4-ol obtained from the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 2-4.

Reference Example E6 8-(chlorosulfonyl)-4-(trifluoromethyl)chroman-4-yl Acetate

By using 8-bromo-chroman-4-one as a starting material, the title compound was obtained, according to the method of Reference Example E5 Steps 1 and 2.

Reference Examples E2 to E4 and E7 to E34

According to the method of Reference Example E1 Steps 1-4, the compounds of Reference Examples E2 to E4 were synthesized. According to the method of Reference Examples E1 Step 3 and 4, the compounds of Reference Examples E7 to E32 were synthesized. According to the method of Reference Example E1 Step 2-4, the compounds of Reference Example E33 and E34 were synthesized. The compounds of Reference Examples E2 to E4 and E7 to E34, and the starting materials are listed in the following table.

TABLE 5-1 Reference Synthesized Example Starting Material Compound E2

E3

E4

E7

E8

E9

E10

E11

E12

E13

E14

E15

TABLE 5-2 Reference Synthesized Example Starting Material Compound E16

E17

E18

E19

E20

E21

E22

E23

E24

E25

E26

E27

E28

E29

TABLE 5-3 Reference Synthesized Example Starting Material Compound E30

E31

E32

E33

E34

Reference Example E35 5-Chloro-6-(pyrrolidine-1-carbonyl)pyridine-2-sulfonyl Chloride

(Step 1) methyl 6-(benzylthio)-3-chloropicolinate

According to the method of Reference Example E1 Step 3, methyl 6-(benzylthio)-3-chloropicolinate was obtained from methyl 6-bromo-3-chloropicolinate.

(Step 2) 6-(benzylthio)-3-chloropicolinic Acid

Methyl 6-(benzylthio)-3-chloropicolinate (1.0 g) obtained in the above Step 1 was dissolved in THF (5.0 mL) and water (1.0 ml), lithium hydroxide (165 mg) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-(benzylthio)-3-chloropicolinic acid (920 mg).

(Step 3) (6-(benzylthio)-3-chloropyridin-2-yl)(pyrrolidin-1-yl)methanone

6-(benzylthio)-3-chloro-picolinic acid (100 mg) obtained in the above Step 2 was dissolved in DMF (2.5 mL), CDI (the 116 mg) was added, the reaction solution was stirred at room temperature for 10 minutes, and then triethylamine (150 μL) and pyrrolidine (60 μL) were added, and the reaction solution was stirred for 12 hours at 50° C. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain (6-(benzylthio)-3-chloropyridin-2-yl)(pyrrolidin-1-yl)methanone (105 mg).

Step 4

The title compound was obtained from (6-(benzylthio)-3-chloropyridin-2-yl)(pyrrolidin-1-yl)methanone obtained in the above Step 3 according to the method of Reference Example E1 Step 4.

Reference Examples E36 to E43

According to the method of Reference Examples E35 Step 3 and E1 Step 4, the compounds of Reference Examples E36 to E43 shown below were synthesized from 6-(benzylthio)-3-chloropicolinic acid obtained from Reference Example E35 Step 2

TABLE 5-4 Reference Synthesized Example Compound E36

E37

E38

E39

E40

E41

E42

E43

Reference Example E44 1-(6-chloro-3-(chlorosulfonyl)-2-methoxyphenyl)ethyl Acetate

(Step 1) 3-bromo-6-chloro-2-methoxybenzaldehyde

According to the method of Reference Example B1 Step 1, 3-bromo-6-chloro-2-methoxybenzaldehyde was obtained from 1-bromo-4-chloro-2-methoxybenzene.

(Step 2) 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol

From 3-bromo-6-chloro-2-methoxybenzaldehyde obtained in the above Step 1, 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol was obtained according to the method of Reference Example A1 Step 1.

(Step 3) 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl Acetate

1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol (1.9 g) obtained in the above Step 2 was dissolved in dichloromethane (20 mL), triethylamine (2.0 mL), N,N-dimethyl-4-aminopyridine (100 mg), and acetic acid anhydride (1.2 mL) were successively added, and the reaction solution was stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl acetate)(2.2 g).

Step 4

From the 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl acetate obtained in the above Step 3, the title compound was obtained according to the method of Reference Examples E1 Steps 3 and 4.

Reference Example E45 1-(5-Chloro-2-(chlorosulfonyl)-3-methoxypyridin-4-yl)ethyl Acetate

According to each of the methods of Reference Example B1 Step 1, Reference Example A1 Step 1, Reference Example E44 Step 3 and Reference Example E1 Steps 3 and 4, the title compound was obtained using 2-bromo-5-chloro-3-methoxypyridine instead of 1-bromo-4-chloro-2-methoxybenzene.

Reference Example E46 2-(6-chloro-3-(chlorosulfonyl)-2-methoxyphenyl)propan-2-yl Acetate

(Step 1) 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanone

To a dichloromethane solution (30 mL) of 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol (2.8 g) obtained by Reference Example E44 Step 2, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (5.4 g) was added, and the reaction solution was stirred for 20 minutes at room temperature. The reaction solution was added dropwise to a mixed solution of a saturated sodium hydrogen carbonate aqueous solution/a sodium hydrogen sulfite solution=1/1 (50 mL) in an ice bath, and the layers were separated. The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanone (2.7 g).

(Step 2) 2-(3-bromo-6-chloro-2-methoxyphenyl)propan-2-yl Acetate

From 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanone obtained in the above Step 1, 2-(3-bromo-6-chloro-2-methoxyphenyl)propan-2-yl acetate was obtained according to the method of Reference Example E1 Steps 1 and 2.

Step 3

From the 2-(3-bromo-6-chloro-2-methoxyphenyl)propan-2-yl acetate (500 mg) obtained in the above Step 2, the title compound was obtained according to the method of Reference Examples E1 steps 3 and 4.

Reference Example E47 4-Chloro-2-(2,2-difluoroethoxy)benzene-1-sulfonyl Chloride

(Step 1) 1-bromo-4-chloro-2-(2,2-difluoroethoxy)benzene

To a DMF solution (5 mL) of 2-bromo-5-chlorophenol (244 mg), potassium carbonate (325 mg) and 2,2-difluoroethyl 4-methylbenzenesulfonate (320 mg) were added, and the reaction solution was stirred for 3 hours at 95° C. The reaction solution was added to an aqueous sodium hydroxide solution (1 M, 20 mL) and extracted with toluene/ethyl acetate=1/1 (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-bromo-4-chloro-2-(2,2-difluoroethoxy)benzene (315 mg).

Step 2

The title compound was synthesized from 1-bromo-4-chloro-2-(2,2-difluoroethoxy)benzene obtained in the above Step 1 according to the method of Reference Examples E1 Steps 3 and 4.

Reference Examples E48 and E49

According to the methods of Reference Example E47 Step 1 and Reference Example E1 Steps 3 and 4, the compounds of Reference Examples E48 and 49 shown below were synthesized. However, regarding Reference Example 48, sodium chlorodifluoroacetate was used instead of 2,2-difluoroethyl 4-methylbenzenesulfonate.

TABLE 5-5 Reference Synthesized Example Starting Material Compound E48

E49

Reference Example E50 4-chloro-2-(isoxazol-5-yl)benzene-1-sulfonyl Chloride

(Step 1) 5-(2-bromo-5-chlorophenyl)isoxazole

An N,N-dimethylformamide dimethyl acetal solution (6.0 mL) of 1-(2-bromo-5-chlorophenyl)ethanone (400 mg) was stirred for 16 hours at 140° C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate). The obtained compound was dissolved in methanol (4.0 mL), hydroxylamine hydrochloride (175 mg) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was added to an aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to purify (eluent: hexane/ethyl acetate) to obtain 5-(2-bromo-5-chlorophenyl)isoxazole (430 mg).

Step 2

From 5-(2-bromo-5-chlorophenyl)isoxazole obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Steps 3,4.

Reference Example E51 Tert-Butyl benzyloxy(5-chloro-2-(chlorosulfonyl)benzoyl)carbamate

(Step 1) N-(benzyloxy)-2-(benzylthio)-5-chlorobenzamide

According to the method of Reference Example E1 Step 3, N-(benzyloxy)-2-(benzylthio)-5-chlorobenzamide was synthesized from N-(benzyloxy)-2-bromo-5-chlorobenzamide.

(Step 2) Tert-Butyl Benzyloxy (2-(benzylthio)-5-chloro-benzoyl)carbamate

To a dichloromethane (10 mL) solution of N-(benzyloxy)-2-(benzylthio)-5-chlorobenzamide (433 mg) obtained from Reference Example 1, N,N-dimethyl-4-aminopyridine (280 mg) and di-tert-butyl dicarbonate (740 mg) were added, and the reaction solution was stirred for 16 hours at 55° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain tert-butylbenzyloxy (2-(benzylthio)-5-chlorobenzoyl)carbamate (549 mg).

Step 3

From the tert-butylbenzyloxy (2-(benzylthio)-5-chlorobenzoyl)carbamate obtained in the above Step 2, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E52 tert-butyl (5-chloro-2-(chlorosulfonyl)benzoyl)(methyl)carbamate

(Step 1) 2-bromo-5-chloro-N-methylbenzamide

From 2-bromo-5-chlorobenzoic acid and methylamine, 2-bromo-5-chloro-N-methylbenzamide was obtained according to the method of Reference Example E35 Step 3.

(Step 2) tert-butyl (2-bromo-5-chlorobenzoyl)(methyl)carbamate

(2-bromo-5-chlorobenzoyl)(methyl)carbamate was obtained from 2-bromo-5-chloro-N-methylbenzamide obtained in the above step 1 according to the method of Reference Example E51 Step 2.

Step 3

From the tert-butyl (2-bromo-5-chlorobenzoyl)(methyl)carbamate obtained in the above Step 2, the title compound was obtained according to the method of Reference Examples E1 steps 3 and 4.

Reference Example E53 methyl 5-chloro-2-(chlorosulfonyl)-4-nitrobenzoate

(Step 1) methyl 2-bromo-5-chloro-4-nitrobenzoate

To a 2-methyl-2-propanol solution (5 mL) of 1-bromo-4-chloro-2-methyl-5-nitrobenzene (1.0 g), water (5 mL), anisole (2.5 mL), and potassium permanganate (1.6 g) were added, and the reaction solution was stirred at 100° C. for 20 hours. The reaction solution was cooled to room temperature, filtered through CELITE, and washed with water (10 mL) and ethyl acetate (10 mL). The combined filtrates were added to hydrochloric acid (1 M, 20 mL), and the layers were separated. The aqueous layer was extracted three times with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.0 mL), dichloromethane (10 mL) and a hexane solution of trimethylsilyldiazomethane (0.6 M, 6.0 mL) were added, and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 2-bromo-5-chloro-4-nitrobenzoate (529 mg).

Step 2

From the methyl 2-bromo-5-chloro-4-nitrobenzoate obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Steps 3 and 4.

Reference Example E54 4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzene-1-sulfonyl Chloride

(Step 1) 5-(2-bromo-5-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one

CDI (310 mg) was added to a THF (6.0 mL) suspension of 2-bromo-5-chlorobenzoic acid (300 mg), and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was ice-cooled, hydrazine⋅monohydrate (160 μL) was added, and the reaction solution was stirred at the same temperature for 20 minutes. The reaction solution was added to water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (6.0 mL), CDI (310 mg) was added, and the reaction solution was stirred at 45° C. for 2 hours. The reaction solution was added to water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(2-bromo-5-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one (300 mg).

Step 2

From the 5-(2-bromo-5-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one obtained in the above Step 1, the title compound is obtained in accordance with the method of Steps 3 and 4 of Reference Example E1.

Reference Example E55 tert-butyl N-tert-butoxycarbonyl-N-(1-(5-chloro-2-chlorosulfonyl-phenyl)cyclopropyl]carbamate

(Step 1) 1-(2-benzylsulfanyl-5-chlorophenyl)cyclopropanamine

To a THF (10 mL) suspension of 2-(benzylthio)-5-chlorobenzonitrile (1.0 g) and titanium tetraisopropoxide (1.3 mL), a diethyl ether solution (3.0 M, 3.0 mL) of methylmagnesium bromide was added dropwise at −78° C., and the reaction solution was stirred at the same temperature for 10 minutes. To the reaction solution, boron trifluoride diethyl ether complex (1.1 mL) was added, and the mixture was further stirred at room temperature for 1 hour, and then water (5 mL) and an aqueous sodium hydroxide solution (1 M, 5 mL) were added to separate layers, the aqueous layer was extracted with diethyl ether (20 mL). The combined organic layers were washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropanamine (490 mg).

(Step 2) tert-butyl N-[1-(2-benzylsulfanyl-5-chloro-phenyl)-cyclopropyl]-N-tert-butoxycarbonyl-carbamate

To a 1,2-dichloroethane solution (10 mL) of 1-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropanamine (490 mg) obtained in the above Step 1, N,N-dimethyl-4-aminopyridine (210 mg) and di-tert-butyl dicarbonate (1.8 g) were added, and the reaction solution was stirred at 50° C. for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane) to obtain tert-butyl N-[l-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropyl]-N-tert-butoxycarbonyl-carbamate (502 mg).

Step 3

From tert-butyl N-[l-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropyl]-N-tert-butoxycarbonyl-carbamate obtained in the above Step 2, the title compound is obtained in accordance with the method of Reference Example E1 step 4.

Reference Example E56 methyl 6-(bis(tert-butoxycarbonyl)amino)-3-chlorosulfonyl-2-methoxy-benzoate

(Step 1) methyl 6-(bis(tert-butoxycarbonyl)amino)-3-bromo-2-methoxybenzoate

From methyl 6-amino-3-bromo-2-methoxybenzoate, methyl 6-(bis(tert-butoxycarbonyl)amino)-3-bromo-2-methoxybenzoate was obtained according to the method of Reference Example E55 Step 2.

Step 2

The title compound was obtained from methyl 6-(bis(tert-butoxycarbonyl)amino)-3-bromo-2-methoxybenzoate obtained in the above step 1 according to the method of Reference Examples E1 Steps 3 and 4.

Reference Example E57 5-Chloro-4,4-difluorochroman-8-sulfonyl Chloride

(Step 1) 8-(benzylthio)-5-chlorochroman-4-one

From 8-bromo-5-chlorochroman-4-one, 8-(benzylthio)-5-chlorochroman-4-one was obtained according to the method of Reference Example E1 Step 3.

(Step 2) 8-(benzylthio)-5-chloro-4,4-difluorochroman

From 8-(benzylthio)-5-chlorochroman-4-one (125 mg) obtained in the above Step 1, 8-(benzylthio)-5-chloro-4,4-difluorochroman was obtained according to the method of Reference Example D61 Step 2.

Step 3

From the 8-(benzylthio)-5-chloro-4,4-difluorochroman obtained in the above Step 2, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E58 tert-Butyl 5-chloro-8-(chlorosulfonyl)-2H-benzo[b] [1,4]oxazin-4(3H)-carboxylate

(Step 1) 8-bromo-5-chloro-3,4-dihydro-2H-benzoxazine

1,2-dibromoethane (500 μL) and potassium carbonate (3.0 g) were added to a DMF solution (6 mL) of 2-amino-6-bromo-3-chlorophenol (1.3 g), and the reaction solution was stirred for 12 hours at 100° C. The reaction solution was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, the layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-3,4-dihydro-2H-benzoxazine (400 mg).

(Step 2) tert-butyl 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate

To dioxane solution (5 mL) of 8-bromo-5-chloro-3,4-dihydro-2H-1,4-benzoxazine (223 mg), 4-dimethylaminopyridine (44 mg), triethylamine (0.25 mL) and di-tert-butyl dicarbamate (458 mg) were added at room temperature, and the reaction solution was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: hexane/ethyl acetate) to obtain tert-butyl 8-bromo-5-chloro-2H-benzo [b][1,4]oxazin-4(3H)-carboxylate (140 mg).

Step 3

From tert-butyl 8-bromo-5-chloro-2H-benzo [b][1,4]oxazin-4(3H)-carboxylate obtained in the above Step 2, the title compound is obtained according to the method of Steps 3 and 4 of Reference Example E1.

Reference Example E59 Tert-Butyl 8-(chlorosulfonyl)-2H-benzo [b][1,4]oxazin-4(3H)-carboxylate

(Step 1) tert-butyl 8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate

From 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine, tert-butyl 8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate was obtained according to the method of Reference Example E58 Step 2.

Step 2

From tert-butyl 8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate obtained in the above Step 1, the title compound was obtained, in accordance with Reference Example E1 Steps 3 and 4.

Reference Example E60 tert-butyl 4-(chlorosulfonyl)-1H-indole-1-carboxylate

From the commercially available tert-butyl 4-bromo-1H-indole-1-carboxylate (Ark Pharm, Inc.), the title compound was obtained according to the method of Reference Example E1 steps 3 and 4.

Reference Example E61 5-chloro-4-ethyl-3,4-dihydro-2H-benzo[b] [1,4]oxazin-8-sulfonyl Chloride

(Step 1) 8-bromo-5-chloro-4-ethyl-2,3-dihydro-1,4-benzoxazine

To a DMSO solution (2.0 mL) of 8-bromo-5-chloro-3,4-dihydro-2H-benzoxazine (380 mg) obtained in Reference Example E58 Step 1, potassium hydroxide (120 mg) and ethyl iodide (100 μL) were added, and the reaction solution was stirred at 100° C. for 2 hours. The reaction solution was allowed to cool to room temperature, a saturated aqueous solution of ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-ethyl-2,3-dihydro-1,4-benzoxazine (105 mg).

Step 2

From the 8-bromo-5-chloro-4-ethyl-2,3-dihydro-1,4-benzoxazine obtained in the above Step 1, the title compound was obtained according to the method of Reference Examples E1 Steps 3 and 4.

Reference Example E62 4-(cyclopropanecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-sulfonyl Chloride

(Step 1) (8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)(cyclopropyl)methanone

Sodium hydride (18 mg) was added to a THF solution (2.0 mL) of 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (62 mg) at 0° C., and the reaction solution was stirred for 30 minutes. Cyclopropanecarbonyl chloride (170 μL) was added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. A saturated ammonium chloride aqueous solution (10 mL) and ethyl acetate (10 mL) were sequentially added to the reaction solution to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give (8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)(cyclopropyl)methanone (87 mg).

Step 2

From (8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)(cyclopropyl)methanone obtained in the above Step 1 according to the method of Steps 3 and 4 of Reference Example E1, the title compound was obtained.

Reference Example E63 5-chloro-4-(2,2-difluoroethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-sulfonyl Chloride

(Step 1) 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one

2-amino-6-bromo-3-chlorophenol (140 mg) was dissolved in THF (2.0 mL), chloroacetyl chloride (100 μL) and sodium hydrogencarbonate (240 mg) were added and the reaction solution was stirred at room temperature for 3 hours. Potassium carbonate (440 mg) was added to the reaction solution, and the mixture was further stirred at 80° C. for 5 hours. The reaction solution was allowed to cool to room temperature, and a saturated aqueous solution of ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to separate layers, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (160 mg).

(Step 2) 8-bromo-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

To a DMF (2.5 mL) solution of 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (69 mg) obtained in the above Step 1, potassium carbonate (420 mg) and 2,2-difluoroethyl paratoluene sulfonate (500 mg) were sequentially added, and the reaction solution was stirred at 100° C. for 3 hours. The reaction solution was allowed to cool to room temperature, and a saturated aqueous solution of ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give 8-bromo-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (85 mg).

(Step 3) 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

From 8-bromo-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one obtained in the above Step 2, 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3 (4H)-one was obtained according to the method of Reference Example E1 Step 3.

Step 4

From the 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, the title compound was obtained in the above Step 3, according to the method of Reference Example E1 Step 4.

Reference Example E64 and E65

From 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one obtained from Reference Example E63 Step 1, the following compounds of reference examples E64 and E65 are synthesized according to method of Reference Example E63 Step 2, and Reference Example E1 Steps 3 and 4.

TABLE 5-6 Reference Example Alkylating agent Synthesized Compound E64 Mel

E65

Reference Example E66 5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonyl Chloride

(Step 1) 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a THF solution (5 mL) of 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (270 mg) obtained from Reference Example 63 Step 3, dimethylsulfide borane (1.0 mL) was added, and the reaction solution was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, methanol (5 mL), ethyl acetate (10 mL), and water (10 mL) were added in order to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (154 mg).

Step 2

From the 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E67 2-cyano-5-(morpholine-4-carbonyl)benzene-1-sulfonyl Chloride

(Step 1) ethyl 3-(benzylthio)-4-cyanobenzoate

Ethyl 3-(benzylthio)-4-cyanobenzoate was obtained from ethyl 3-bromo-4-cyanobenzoate according to the method of Reference Example E1 Step 3.

(Step 2) 6-(benzylthio)-4-cyano-benzoic Acid

An aqueous sodium hydroxide solution (3 M, 4.0 mL) was added to a THF (4.0 mL) solution of ethyl 3-(benzylthio)-4-cyanobenzoate (344 mg) obtained in the above Step 1, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-(benzylthio)-4-cyanobenzoic acid (210 mg).

(Step 3) 2-(benzylthio)-4-(morpholine-4-carbonyl)benzonitrile

Using 6-(benzylthio)-4-cyano-benzoic acid obtained from the above Step 2 and morpholine, 2-(benzylthio)-4-(morpholine-4-carbonyl)benzonitrile was obtained according to Reference Example E35 Step 3.

Step 4

From the 2-(benzylthio)-4-(morpholine-4-carbonyl)benzonitrile obtained in the above Step 3, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E68 2-cyano-5-(dimethylcarbamoyl)benzene-1-sulfonyl Chloride

(Step 1) 2-(benzylthio)-4-cyano-N,N-dimethylbenzamide

According to the method of Reference Example E35 Step 3, from 6-(benzylthio)-4-cyanobenzoic acid obtained in Reference Example E67 Step 2 and dimethylamine, 2-(benzylthio)-4-cyano-N,N-dimethylbenzamide was obtained.

Step 2

From the 2-(benzylthio)-4-cyano-N,N-dimethylbenzamide obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E69 4-chloro-2-cyano-5-(dimethylcarbamoyl)benzene-1-sulfonyl Chloride

The title compound was synthesized from methyl 5-bromo-2-chloro-4-cyanobenzoate according to each of the methods of Reference Example E1 Step 3, Reference Example E67 Step 2, Reference Example E35 Step 3 and Reference Example E1 Step 4.

Reference Example E70 tert-butyl (5-chloro-8-(chlorosulfonyl)chroman-4-yl)carbamate

(Step 1) 8-benzyl-sulfanyl-5-chlorochroman-4-one

From 8-bromo-5-chlorochroman-4-one, 8-benzylsulfanyl-5-chlorochroman-4-one was obtained according to the method of Reference Example E1 Step 3.

(Step 2) 8-benzyl-sulfanyl-5-chlorochroman-4-amine

8-benzylsulfanyl-5-chlorochroman-4-one (460 mg) obtained in the above Step 1 was dissolved in methanol (3.0 mL), ammonium chloride (1.2 g) was added, and the reaction solution was stirred at room temperature for 2 hours. Sodium cyanoborohydride (670 mg) was added to the reaction solution, and the mixture was further stirred at 80° C. for 14 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL), an aqueous sodium hydroxide solution (5 M, 10 mL) and chloroform (20 mL) were added successively to the reaction solution to separate layers, and the aqueous layer was extracted twice with chloroform (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 8-benzylsulfanyl-5-chlorochroman-4-amine (216 mg).

(Step 3) tert-butyl (8-(benzylthio)-5-chlorochroman-4-yl)carbamate

From 8-benzylsulfanyl-5-chloro-chroman-4-amine (216 mg) obtained in the above Step 2, tert-butyl (8-(benzylthio)-5-chlorochroman-4-yl)carbamate was obtained according to Reference Example E58 Step 2.

Step 4

From the tert-butyl (8-(benzylthio)-5-chlorochroman-4-yl)carbamate obtained in the above Step 3, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E71 4-acetamido-5-chlorochroman-8-sulfonyl Chloride

(Step 1) N-(8-bromo-5-chlorochromanon-4-yl)acetamide

8-Bromo-5-chlorochromanon-4-amine (250 mg) was dissolved in DMF (2.0 mL) and THF (7.0 mL), N,N-dimethyl-4-aminopyridine (45 mg), triethylamine (400 μL) and acetic anhydride (200 μL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain N-(8-bromo-5-chlorochromanon-4-yl)acetamide (260 mg).

Step 2

From the N-(8-bromo-5-chlorochromanon-4-yl)acetamide obtained in the above Step 1, the title compound was obtained according to the method of Reference Examples E1 steps 3 and 4.

Reference Example E72 1-(3-chloro-6-(chlorosulfonyl)pyridin-2-yl)-2,2,2-trifluoroethylacetate

(Step 1) 1-(6-bromo-3-chloropyridin-2-yl)-2,2,2-trifluoroethanol

Cesium fluoride (700 mg) and (trifluoromethyl)trimethylsilane (700 μL) were added to a THF (10 mL) solution of 6-bromo-3-chloropicolinaldehyde (770 mg), and the reaction solution was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(6-bromo-3-chloropyridin-2-yl)-2,2,2-trifluoroethanol (600 mg).

Step 2

From 1-(6-bromo-3-chloropyridin-2-yl)-2,2,2-trifluoroethanol obtained in the above Step 1, according to the method of Reference Examples E44 Step 3 and E1 Steps 3 to 4, the title compound was obtained.

Reference Example E73 methyl 5-bromo-2-(chlorosulfonyl)nicotinate

(Step 1) methyl 2-(benzylthio)-5-bromo-nicotinate

Sodium hydride (285 mg) was added to a THF (5.0 mL) solution of benzyl mercaptan (700 μL) at 0° C., and the reaction solution was stirred at room temperature for 15 min. A THF (3.0 mL) solution of methyl 2,5-dibromonicotinate (1.59 g) was added dropwise to the reaction solution, and the mixture was stirred at 0° C. for 20 minutes. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 2-(benzylthio)-5-bromonicotinate (1.5 g).

Step 2

From the methyl 2-(benzylthio)-5-bromonicotinate obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example F1 5-((1S,2R)-1-Amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one Monohydrochloride

(Step 1) (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic Acid

Water (9 mL), 1,4-dioxane (9 mL) and triethylamine (955 μL) were sequentially added to (2S, 3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (515 mg) obtained in Reference Example D1, and the mixture was cooled to 0° C. Di-tert-butyl dicarbonate (650 mg) was added to the reaction solution at the same temperature, and the mixture was stirred for 45 minutes. The reaction solution was added to hydrochloric acid (1 M, 20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (745 mg).

(Step 2) tert-butyl ((1 S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)carbamate

To a THF solution (14.0 mL) of (2S, 3R)-2-(tert-butoxycarbonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (440 mg) obtained in the above Step 1, CDI (302 mg) was added, and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was cooled to 0° C., hydrazine⋅monohydrate (200 μL) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. CDI (560 mg) was added to a 1,4-dioxane (14 mL) solution of the obtained residue, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography by purification (eluent: hexane/ethyl acetate) to obtain tert-butyl ((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiiazol-2-yl)propyl)carbamate (356 mg).

Step 3

tert-butyl ((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)carbamate (550 mg) obtained in the above Step 2 was dissolved in hydrochloric acid-1,4-dioxane (4 M, 5.0 mL), and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound.

Reference Examples F2 to F10

According to the method of Reference Example F1 Steps 1 to 3, the following compounds of Reference Examples F2 to F10 were synthesized.

TABLE 6 Starting Material (Reference example number or Reference structural Example formula) Synthesized Compound F2 Reference Example D6

F3 Reference Example D3

F4 Reference Example D13

F5 Reference Example D10

F6 Reference Example D41

F7 Reference Example D4

F8 Reference Example D5

F9 Reference Example D45

F10 Reference Example D61

Example 1 5-bromo-2-(N-((1 S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide Step 1

To a 1,4-dioxane (5.0 mL) solution and water (5.0 mL) of (2S, 3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (300 mg) obtained in Reference Example D1, triethylamine (570 μL) was added and then cooled to 0° C. 4-Bromo-2-cyanobenzene-1-sulfonyl chloride (362 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 45 minutes. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain (2S, 3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (465 mg).

Step 2

To a THF (5.0 mL) solution of (2S, 3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (465 mg) obtained in the above Step 1, CDI (210 mg) was added, and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was cooled to 0° C., hydrazine⋅monohydrate (200 μL) was added, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

CDI (211 mg) was added to a 1,4-dioxane (4.0 mL) solution of the obtained residue, and the reaction solution was stirred at 45° C. for 1 hour. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (386 mg).

Step 3

To a DMSO (5.0 mL) solution of 4-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (386 mg) obtained in the above Step 2, hydrogen peroxide water (1.0 mL) and potassium carbonate (420 mg) were added sequentially in an ice bath, and the reaction solution was stirred at 60° C. for 2.5 hours. The reaction solution was slowly added to hydrochloric acid (1 M, 15 mL) in an ice bath and then extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 2 to 128

Compounds of Examples 2 to 43 were synthesized according to the method of Example 1 Steps 1 to 3. Compounds of Examples 44 to 128 were synthesized according to the method of Example 1 Step 1 and 2. The necessary raw materials are listed in the following table.

TABLE 7-1 Example Starting Material ArSO2Cl Name of the Synthesized Compound 2 Reference E22 6-Chloro-3-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo- Example D10 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinamide 3 Reference Example D6

5-chloro-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 4 Reference Example D6

5-bromo-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 5 Reference Example D1

5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 6 Reference Example D3

5-chloro-2-(N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1, 3, 4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 7 Reference Example D7

5-chloro-2-(N-((1S,2R)-2-(5-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 8 Reference Example D20

5-chloro-2-(N-((1S,2R)-2-(8-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 9 Reference Example D8

5-chloro-2-(N-((1S,2R)-2-(3-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 10 Reference Example D1

2-(N-((1S,2R)-2-(3-6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-methylbenzamide 11 Reference Example D45

5-chloro-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide

TABLE 7-2 Example Starting Material ArSO2Cl Name of the Synthesized Compound 12 Reference Example D3

2-(N-((1S,2R)-2-(2-Fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-methylbenzamide 13 Reference Example D46

5-chloro-2-(N-((1S,2R)-2-(2,3-difluoro-5,6-dimethylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl) sulfamoyl)benzamide 14 Reference Example D4

5-chloro-2-(N-((1S,2R)-2-(3 chloro-6-fluoro-2-methylphenyl)-1- (5oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 15 Reference Example D3

5-bromo-2-(N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 16 Reference Reference Example E20 5-Cyclopropyl-2-(N-((1S,2R)-2-(6-Fluoro-2,3-dimethylphenyl)-1- Example D1 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 17 Reference Example D15

5-chloro-2-(N-((1S)-2-(2-chloro-6-fluoro-3-methylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 18 Reference Reference Example E21 5-Ethyl-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example D1 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 19 Reference Reference Example E22 6-Chloro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example D1 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinamide 20 Reference Example D1

2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 21 Reference Example D16

5-chloro-2-(N-((15,2R)-2-(2-fluoro-5-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 22 Reference Example D17

5-chloro-2-(N-((1S,2R)-2-(2-fluoro-6-methylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide

TABLE 7-3 Example Starting Material ArSO2Cl Name of the Synthesized Compound 23 Reference Example D18

5-chloro-2-(N-((1S,2S)-2-(2-fluoro-6-methylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 24 Reference Example D37

5-chloro-2-(N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-(o-tolyl)propyl)sulfamoyl)benzamide 25 Reference Example D4

5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro 2 methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 26 Reference Example D47

5-chloro-2-(N-((1S,2R)-2-(3-cyclopropy1-6-fluoro-2-methylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 27 Reference Example D48

5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2-methyl-3-(trifluoromethyl)phenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 28 Reference Example D19

5-chloro-2-(N-((1S,2R)-2-(3,6-difluoro-2-methylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 29 Reference Example D49

3-((1S,2R)-1-(4-chloro -2-methoxyphenylsulfonamido)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propan-2-yl)-4-fluoro-2-methylbenzamide 30 Reference Example D5

2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chlorobenzamide 31 Reference Reference Example E18 3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example D1 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinamide 32 Reference Example D2

5-chloro-2-(N-((1S,2S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 33 Reference Example D57

5-chloro-2-(N-((1R,2S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide

TABLE 7-4 34 Reference Example D58

5-chloro-2-(N-((1R,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 35 Reference Example D5

5-bromo-2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 36 Reference Reference Example E67 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(morpholine-4-carbonyl)benzamide 37 Reference Reference Example E68 3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N1,N1-dimethylterephthalamide 38 Reference Reference Example E16 4-carbamoyl-2-chloro-5-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- Example D1 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid 39 Reference Reference Example E69 2-chloro-5-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N1,N1-dimethyl terephthalamide 40 Reference Reference Example E32 2-chloro-5-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example D1 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)isonicotinamide 41 Reference Example D1

2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5 dihydro- 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-(trifluoromethyl)benzamide 42 Reference Example D5

2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-(trifluoromethyl)benzamide 43 Reference Example D44

5-chloro-2-[[(1S,2R)-3,3,3-trideuterio-2-(6-fluoro-2,3-dimethylphenyl)-1- (2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]sulfamoyl]benzamide 44 Reference Example D11

4-bromo-N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide

TABLE 7-5 Example Starting Material ArS02C1 Name of the Synthesized Compound 45 Reference Example D27

N-((1S,2R)-2-(benzo[b]triophen-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propy1)-4-bromobenzenesulfonamide 46 Reference Example D11

2,4-dichloro-N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 47 Reference Example D21

2-chloro-4-cyclopropyl-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-(5,6,7,8-tetrahydronaphthalen-1- yl)propyl)benzenesulfonamide 48 Reference Example D51

5-bromo-N-((1S)-2-(3-methyl-2,3-dihydro-1H-inden-4-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-2-sulfonamide 49 Reference Example D22

N-((1S,2R)-2-(9H-fluoren-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)propyl)-5-bromopyridine-2-sulfonamide 50 Reference Example D23

N-((1S,2R)-2-(9H-fluoren-4-yl)-1-(5-oxo-4,5 dihydro-1,3,4-oxadiazol- 2-yl)propyl)-5-bromopyridine-2-sulfonamide 51 Reference Example D11

N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)propyl)-4-nitrobenzene sulfonamide 52 Reference Example D21

5-chloro-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2- (5,6,7,8-tetrahydronaphthalen-1-yl)propyl)pyridine-2-sulfonamide 53 Reference Example D21

4-bromo-3-methoxy-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2- (5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzene sulfonamide 54 Reference Example D21

4-chloro-2-nitro-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)-2-(5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzene sulfonamide 55 Reference Example D21

2,4-dimethoxy-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)-2-(5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzene sulfonamide

TABLE 7-6 Example Starting Material ArS02C1 Name of the Synthesized Compound 56 Reference Example D24

4-chloro-N-((1S,2R)-2-(6-fluoro-naphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 57 Reference Example D21

2-methoxy-4-nitro-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)-2-(5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzenesulfonamide 58 Reference Example D21

methyl 4-methoxy-5-(N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-(5,6,7,8-tetrahydronaphthalen-1- yl)propyl)sulfamoyl)thiophene-3-carboxylate 59 Reference Example D10

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2yl)propyl)benzo[c][1,2,5]thiadiazole-4-sulfonamide 60 Reference Example D10

4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-fluorobenzenesulfonamide 61 Reference Example D10

3-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-fluorobenzenesulfonamide 62 Reference Example D33

N-((1S,2R)-2-(benzo[b]thiophen-3-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide 63 Reference Example D40

N-((1S,2R)-2-(benzo[d]thiazol-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide 64 Reference Example D30

4-chloro-N-((1S,2R)-2-(2,3-dihydrobenzofuran-7-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 65 Reference Example D31

4-chloro-2-methoxy-N-((1S,2R)-2-(2-methyl naphthalen-1-yl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 66 Reference Example D29

4-chloro-N-((1S,2R)-2-(2,3-dihydrobenzofuran-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

TABLE 7-7 Example Starting Material ArS02C1 Name of the Synthesized Compound 67 Reference Example D53

4-chloro-2-methoxy-N-((1S,2R)-2-(2-methyl-2,3-dihydro-1H-inden-4- yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 68 Reference Example D10

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)naphthalene-1-sulfonamide 69 Reference Example D52

4-chloro-2-methoxy-N-((1S,2S)-2-(3-methyl-2,3-dihydro-1H-inden-4- yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 70 Reference Example D28

4-chloro-2-methoxy-N-((1S,2R)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 71 Reference Example D13

4-chloro-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 72 Reference Example D35

4-chloro-2-methoxy-N-((1S,2R)-2-(3-methy1-2,3-dihydrobenzofuran- 4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide 73 Reference Example D36

4-chloro-2-methoxy-N-((1S,2S)-2-(3-methy1-2,3-dihydrobenzofuran- 4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide 74 Reference Example D34

4-chloro-N-((1S)-2-(2,3-difluorophenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 75 Reference Example D32

4-chloro-N-((1S,2R)-2-(3-fluoro-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 76 Reference Example D3

4-chloro-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 77 Reference Example D9

4-chloro-N-((1S,2R)-2-(4-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

TABLE 7-8 Example Starting Material ArS02C1 Name of the Synthesized Compound 78 Reference Example D55

(S)-4-chloro-2-methoxy-N-(2-(8-methylnaphthalen-1-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)benzenesulfonamide 79 Reference Example D38

4-chloro-N-((1S)-2-(2,6-difluoro-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propy1)-2-methoxybenzenesulfonamide 80 Reference Example D39

4-chloro-N-((1S)-2-(2-fluoro-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 81 Reference Reference Example E57 5-chloro-4,4-difluoro-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1-(5- Example D13 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8-sulfonamide 82 Reference Example D25

4-chloro-N-((1S,2R)-2-(5-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 83 Reference Example D1

4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 84 Reference Example D1

4-chloro-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 85 Reference Example D14

4-chloro-N-((1S,2R)-2-(2-isopropyl-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 86 Reference Example D12

4-chloro-N-((1S,2R)-2-(3-ethyl-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 87 Reference Example D42

4-chloro-N-((1S,2R)-2-(2-ethyl-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 88 Reference Reference Example E7 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example D1 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide

TABLE 7-9 Example Starting Material ArS02C1 Name of the Synthesized Compound 89 Reference Example D50

N-((1S)-2-(2-bromo-5,6-difluoro-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide 90 Reference Example D46

4-chloro-N4(1S,2R)-2-(2,3-difluoro-5,6-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 91 Reference Reference 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E50 1,3,4-oxadiazol-2-yl)propyl)-2-(isoxazol-5-yl)benzenesulfonamide 92 Reference Example D1

4-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 93 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol- Example D1 Example E64 2-yl)propyl)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide 94 Reference Reference 5-chloro-4-ethyl-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E61 1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo [b][1,4]oxazine-8-sulfonamide 95 Reference Reference 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E2 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methylchroman-4-yl acetate 96 Reference Example D45

5-bromo-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 97 Reference Reference N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- Example D1 Example E23 oxadiazol-2-yl)propyl)-2,2-dimethyl-4-oxochroman-8-sulfonamide 98 Reference Example D1

2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide

TABLE 7-10 Example Starting Material ArS02C1 Name of the Synthesized Compound 99 Reference Reference 4-(cyclopropanecarbonyl)-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E62 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine-8-sulfonamide 100 Reference Reference 5-chloro-8-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro- Example D4 Example E2 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methylchroman-4-yl acetate 101 Reference Reference 5-chloro-4-(2,2-difluoroethyl)-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E63 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide 102 Reference Reference 5-chloro-4-(2,2-difluoroethyl)-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E66 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propy1)-3,4- dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide 103 Reference Example D1

methyl-5-chloro-2(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate 104 Reference Example D49

4-chloro-N-((1S,2R)-2-(3-cyano-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 105 Reference Reference 5-chloro-6-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example D1 Example E18 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-2-sulfonamide 106 Reference Reference 8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E6 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(tifluoromethyl)chroman-4-yl acetate 107 Reference Reference 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example D1 Example E25 dihydro-1,3,4-oxadiazol-2-yl)propyl)-8-oxo-5,6,7,8-tetrahydronaphthalene-1-sulfonamide 108 Reference Reference 2-(6-chloro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E46 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2-methoxyphenyl)propan-2-yl acetate

TABLE 7-11 Example Starting Material ArS02C1 Name of the Synthesized Compound 109 Reference Reference methyl 3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- Example D1 Example E10 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinate 110 Reference Example D1

2,6-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 111 Reference Example D1

4-chloro-2,6-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 112 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example D1 Example E27 dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-methoxypyridine-2-sulfonamide 113 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E37 1,3,4-oxadiazol-2-yl)propyl)-6-(morpholine-4-carbonyl)pyridine-2-sulfonamide 114 Reference Reference 5-chloro-N-((1S,2R) 2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E35 1,3,4-oxadiazol-2-yl)propyl)-6-(pyrrolidine-1-carbonyl)pyridine-2-sulfonamide 115 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- Example D1 Example E43 oxadiazol-2-yl)propyl)-6-(6-azaspiro[3.4]octane-6-carbonyl)pyridine-2-sulfonamide 116 Reference Reference 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3- Example D1 Example E39 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-2-sulfonamide 117 Reference Reference 6-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3- Example D1 Example E40 dimethylphenyl)-1-(5-oxo-4,5 dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-2-sulfonamide 118 Reference Reference methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E11 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate

TABLE 7-12 Example Starting Material ArS02C1 Name of the Synthesized Compound 119 Reference Reference methyl 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- Example D1 Example E73 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate 120 Reference Reference 1-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E45 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxypyridin-4-yl)ethyl acetate 121 Reference Reference methyl 5-chloro-4-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E28 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate 122 Reference Reference methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example D1 Example E14 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methoxybenzoate 123 Reference Reference 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example D1 Example E5 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(trifluoromethyl)chroman-4-yl acetate 124 Reference Reference N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro- Example D5 Example E7 1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-oxochroman-8-sulfonamide 125 Reference Example D59

(S)-4-chloro-N-(2-(6-fluoro-2,3-dimethylphenyl)-2-methyl-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 126 Reference Example D54

(S)-4-chloro-N-(2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide 127 Reference Example D60

(S)-4-chloro-N-((1-(6 fluoro-2,3-dimethylphenyl)cyclopropyl)(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-2-methoxybenzenesulfonamide 128 Reference Example D43

4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)butyl)-2-methoxybenzenesulfonamide

Example 129 5-Chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methyl-d3-chroman-4-yl Acetate

To a pyridine (1.5 mL) solution of 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (45 mg) obtained from Reference Example F1, 5-chloro-8-(chlorosulfonyl)-4-methyl-d3-chroman-4-ylacetate (80 mg) obtained in Reference Example E1 was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (59 mg) as a 1:1 diastereomer mixture.

Examples 130 to 185

According to the method of Example 129, the following compounds of Examples 130 to 185 were synthesized. The necessary raw materials are listed in the following table.

TABLE 8-1 Example Starting Material ArS02C1 Name of the Synthesized Compound 130 Reference Example F6

5-bromo-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)-2-(quinoline-8-yl)propyl)pyridine-2-sulfonamide 131 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-fluoro-3-(methylsulfonyl)benzenesulfonamide 132 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)quinoline-8-sulfonamide 133 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-2-(isoxazol-4-yl)benzenesulfonamide 134 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 135 Reference Example F5

4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-ethylbenzenesulfonamide 136 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-3-methylquinoline-8-sulfonamide 137 Reference Example F5

4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 138 Reference Example F5

2-(difluoromethoxy)-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide

TABLE 8-2 Example Starting Material ArSO2Cl Name of the Synthesized Compound 139 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b]thiophene-6-sulfonamide 1,1-dioxide 140 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-5,6,7,8-tetrahydronaphthalene-1- sulfonamide 141 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-2-methoxypyridine-3-sulfonamide 142 Reference E34 1-(3-chloro-6-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo- Example F5 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)pyridin-2- yl)ethylacetate 143 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-5-nitroquinoline-8-sulfonamide 144 Reference Reference 1-(6-chloro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example F1 Example E44 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2- methoxyphenyl)ethyl acetate 145 Reference Reference 4-chloro-2-(2,2-difluoroethoxy)-N-((1S,2R)-2-(6-fluoro-2,3- Example F1 Example E47 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide 146 Reference Reference 4-chloro-2-(difluoromethoxy)-N-((1S,2R)-2-(6-fluoro-2,3- Example F1 Example E48 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide 147 Reference Reference 2-acetyl-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5 Example F1 Example E19 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 148 Reference Example F1

6-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-2-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxypyridine-3- sulfonamide

TABLE 8-3 Example Starting Material ArSO2Cl Name of the Synthesized Compound 149 Reference E54 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)benzenesulfonamide 150 Reference Example F2

N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-methylbenzenesulfonamide 151 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-methylbenzenesulfonamide 152 Reference E60 N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example F1 1,3,4-oxadiazol-2-yl)propyl)-1H-indole-4-sulfonamide 153 Reference Example F1

5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)quinoline-8-sulfonamide 154 Reference Example F1

6-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methoxypyridine-3- sulfonamide 155 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E38 dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2-oxa-6-azaspiro[3.4]octane- 6-carbonyl)pyridine-2-sulfonamide 156 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E42 dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2-oxa-7- azaspiro[3.5]nonane-7-carbonyl)pyridine-2-sulfonamide 157 Reference Reference N-(5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example F1 Example E71 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)chroman-4- yl)acetamide 158 Reference Example F1

5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)thiophene-2-sulfonamide

TABLE 8-4 Example Starting Material ArSO2Cl Name of the Synthesized Compound 159 Reference Reference 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E8 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide 160 Reference Example F1

2-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-1-methyl-1H-imidazole-4- sulfonamide 161 Reference Example F1

4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1H-tetrazol-5- yl)benzenesulfonamide 162 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-oxoindoline-5-sulfonamide 163 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1,3-dioxoisoindoline-5-sulfonamide 164 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- sulfonamide 165 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-sulfonamide 166 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b]thiophene-6- sulfonamide 1,1-dioxide 167 Reference Reference 8-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- Example F8 Example E2 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chloro-4- methylchroman-4-yl-acetate

TABLE 8-5 Example Starting Material ArSO2Cl Name of the Synthesized Compound 168 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-5-sulfonamide 169 Reference Example F1

4-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-3- (methylsulfonyl)benzenesulfonamide 170 Reference Example F1

2,4-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6- methoxybenzenesulfonamide 171 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3-(piperidin-1- ylsulfonyl)benzenesulfonamide 172 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dioxo-1,2,3,4- tetrahydroquinoxaline-6-sulfonamide 173 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b][1,4]dioxin-6- sulfonamide 174 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-8-oxo-5,6,7,8-tetrahydronaphthalene-2- sulfonamide 175 Reference Example F1

N-(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1-oxo-1,3-dihydroisobenzofuran-4- sulfonamide 176 Reference Example F1

4-chloro-N1-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)benzene-1,3-disulfonamide

TABLE 8-6 Example Starting Material ArSO2Cl Name of the Synthesized Compound 177 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 178 Reference Example F1

methyl 2,6-difluoro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate 179 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-6-sulfonamide 180 Reference Reference methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5 Example F1 Example E53 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4- nitrobenzoate 181 Reference Example F1

N-(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1H-benzo[d][1,2,3]triazole-5- sulfonamide 182 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yll)propyl)-1H-indazole-5-sulfonamide 183 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)chroman-6-sulfonamide 184 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1-methyl-1,2,3,4-tetrahydroquinoline-7- sulfonamide 185 Reference Example F10

(S)-4-chloro-N-(2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)allyl)-2-methoxybenzenesulfonamide

TABLE 8-7 Example Starting Material ArSO2Cl Name of the Synthesized Compound 338 Reference Example F1

4-bromo-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- (trifluoromethoxy)benzenesulfonamide 339 Reference Example F1

4-bromo-2,5-difluoro-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 340 Reference Example F1

N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-nitrobenzenesulfonamide 341 Reference Example F1

4-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 342 Reference Example F1

4-cyano-N-(1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 343 Reference Example F1

4-bromo-3-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide

Example 186 2,4-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1

Methyl 3-(chlorosulfonyl)-2,6-difluorobenzoate (33 mg) was added to a pyridine (1.0 mL) solution of 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (20 mg) obtained from Reference Example F1, and the reaction solution was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 2,6-difluoro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (12.5 mg).

Step 2

To a THF (2.0 mL) solution of methyl 2,6-difluoro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (12.5 mg) obtained from the above Step 1, a diethyl ether (3.0 M, 84 μL) solution of methylmagnesium bromide was added dropwise at 0° C., and the reaction solution was stirred for 1 hour at room temperature. A saturated ammonium chloride aqueous solution (10 mL) was added dropwise in an ice bath, ethyl acetate (10 mL) was added, and the layers were separated. The organic layer was washed successively with hydrochloric acid (1 M, 10 mL), water (10 mL) and saturated saline (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound.

Examples 187 to 195

According to the method of Example 186, the following compounds of Examples 187 to 195 were synthesized. The necessary raw materials are listed in the following table.

TABLE 9 Starting Example Material ArSO2Cl Name of the Synthesized Compound 187 Reference Example F5

4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-(2-hydroxypropan-2- yl)benzenesulfonamide 188 Reference Example F5

4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2- yl)benzenesulfonamide 189 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-2,4-difluoro-3-(2-hydroxypropan-2- yl)benzenesulfonamide 190 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-(2-hydroxypropan-2-yl)-3-methoxythiophene-2- sulfonamide 191 Reference Example F5

N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)-2,4- dimethoxybenzenesulfonamide 192 Reference Reference 5-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- Example F5 Exmple E10 1,3,4-oxadiazol-2-yl)propyl)-6-(2-hydroxypropan-2-yl)pyridine-2- sulfonamide 193 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E10 dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2-hydroxypropan-2-yl)pyridine-2- sulfonamide 194 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-8-hydroxy-8-methyl-5,6,7,8- tetrahydronaphthalene-2-sulfonamide 195 Reference Example F1

N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-6-sulfonamide

Example 196 5-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(2-hydroxypropan-2-yl)benzamide Step 1

From 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (60 mg) obtained from Reference Example F1 and methyl 2-fluoro-5-(chlorosulfonyl)-4-cyanobenzoate (94 mg) obtained in Reference Example E15, in accordance with the method of Example 129, methyl 4-(cyano-2-fluoro-5 (N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (49 mg) was obtained.

Step 2

From methyl 4-cyano-2-fluoro-5-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (49 mg) obtained from the above Step 1, according to the method of Example 186 Step 2, 2-cyano-4-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-(2-hydroxypropan-2-yl)benzenesulfonamide (27.5 mg) was obtained.

Step 3

From 2-cyano-4-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-(2-hydroxypropan-2-yl)benzenesulfonamide (27.5 mg) obtained from the above Step 2, according to the method of Example 1 Step 3, the title compound was obtained.

Examples 197 to 199

According to the method of Example 129, Example 186 Step 2, Example 1 Step 3, the following compounds of Examples 197 to 199 were synthesized. The necessary raw materials are listed in the following table. However, for Example 199, the synthesis was carried out using 1-propynyl magnesium bromide instead of methyl magnesium bromide.

TABLE 10 Starting Example Material ArSO2Cl Name of the Synthesized Compound 197 Reference Reference 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example F1 Example E13 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(2-hydroxypropan-2-yl)benzamide 198 Reference Reference 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E16 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(2-hydroxypropan-2- yl)benzamide 199 Reference Reference 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example F1 Example E13 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(hydroxyhepta-2,5-diyn-4- yl)benzamide

Example 200 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide Isomer A and Isomer B

1:1 diastereomer mixture of 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methyl-d3-chroman-4-yl acetate (59 mg) obtained from Example 129 was dissolved in methanol (2.0 mL) and water (1.0 mL), lithium hydroxide (5 mg) was added, and the reaction solution was stirred at 55° C. for 1 hour. After concentrating the reaction solution, hydrochloric acid (1 M, 10 mL) and ethyl acetate (10 mL) were added to the residue, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL), and the combined organic layers were washed with saturated saline (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile), and the fractions were concentrated to give each of two diastereomeric products. The substance eluted first was designated Compound A, and the substance eluted later was designated as Compound B.

Examples 201 to 229

According to the method of Example 200, the following compounds of Examples 201 to 229 were synthesized. In the case of separating the diastereomers, the previously eluted compound was designated as A and the later eluted compound as B. The ratio of diastereomers is 1:1 mixture unless otherwise specified. The necessary raw materials are listed in the following table.

TABLE 11-1 Starting Example Material ArSO2Cl Name of the Synthesized Compound 201 Reference Reference 2,4-dichloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- Example Example E33 dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1- F5 hydroxyethyl)benzenesulfonamide (diastereomer mixture) 202 Reference Reference 5-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- Example Example E34 1,3,4-oxadiazol-2-yl)propyl)-6-(1-hydroxyethyl)pyridine-2-sulfonamide F5 (diastereomer mixture) 203 Reference Reference 4-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- Example Example E44 oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2- F2 methoxybenzenesulfonamide (diastereomer mixture) 204 Reference Reference 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5 Example Example E44 dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2- F1 methoxybenzenesulfonamide (diastereomer mixture) 205 Reference Reference 4-chloro-N-((1S,2R)-2-(2-fluoronaphthalene-1-yl)-1-(5-oxo-4,5-dihydro- Example Example E44 1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2- F3 methoxybenzenesulfonamide (diastereomer mixture) 206A Reference Reference 4-chloro-N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- Example Example E44 dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2- F9 methoxybenzenesulfonamide 207-A Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- 207-B Example Example E2 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8- F1 sulfonamide 208A Reference Reference 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- 208-B Example Example E44 dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2- F1 methoxybenzenesulfonamide 209A Reference Reference 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- 209-B Example Example E2 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8- F7 sulfonamide 210 Reference Example F1

5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid

TABLE 11-2 Starting Example Material ArSO2Cl Name of the Synthesized Compound 211A Reference Reference N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- Example F1 Example E6 oxadiazol-2-yl)propyl)-4-hydroxy-4-(tifluoromethyl)chroman-8- sulfonamide 212 Reference Reference 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E46 dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)-2- methoxybenzenesulfonamide 213 Reference Reference 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E11 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinic acid 214 Reference Reference 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E73 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinic acid 215 Reference Reference 3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E10 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinic acid 216 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E45 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-(1-hydroxyethyl)-3- methoxypyridine-2-sulfonamide (diastereomer mixture) 217 Reference Reference 5-chloro-4-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- Example F1 Example E28 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid 218 Reference Reference 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E12 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methylbenzoic acid 219 Reference Reference 5-chloro-3-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- Example F1 Example E29 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid 220A Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- 220-B Example F1 Example E5 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4- (tifluoromethyl)chroman-8-sulfonamide 221 Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E72 dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2,2,2-trifluoro-1- hydroxyethyl)pyridine-2-sulfonamide (diastereomer mixture)

TABLE 11-3 Starting Example Material ArSO2Cl Name of the Synthesized Compound 222A Reference Reference N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro- 222-B Example F8 Example E2 1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methylchroman-8- sulfonamide 223 Reference Reference 7-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- Example F1 Example E17 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2,3-dihydrobenzo[b][1,4]dioxin-6- Carboxylic Acid 224A Reference Reference 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- 224-B Example F1 Example E3 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8- sulfonamide 225A Reference Reference N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- Example F1 Example E4 oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-5-(tifluoromethyl)chroman-8- sulfonamide 226A Reference Reference N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro- 226-B Example F8 Example E1 1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methyl-d3-chroman-8- sulfonamide

TABLE 11-4 Starting Example Material ArSO2Cl Name of the Synthesized Compound 227A Reference Reference N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro- 227-B Example F8 Example E3 1,3,4-oxadiazol-2-yl)propyl)-5-fluoro-4-hydroxy-4-methyl-d3-chroman-8- sulfonamide 228A Reference Reference 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- 228-B Example F7 Example E1 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8- sulfonamide 229A Reference Reference N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro- 229-B Example F7 Example E3 1,3,4-oxadiazol-2-yl)propyl)-5-fluoro-4-hydroxy-4-methylchroman-8- sulfonamide

Example 230 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide Isomer A and Isomer B Step 1

Using 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (40 mg) obtained from Reference Example F1 and 5-fluoro-4-oxochroman-8-sulfonyl chloride (60 mg) obtained from Reference Example E8, 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (44 mg) was obtained in accordance with the method of Example 129.

Step 2

Sodium borohydride (13.5 mg) was added to an ethanol (2.0 mL) solution of 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (44 mg) obtained from the above Step 1 and the reaction solution was stirred at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added to the residue, separated, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile), and the fractions were concentrated to obtain each of two diastereomeric products. The substance eluted first was designated as Compound A, and the substance eluted later was designated as Compound B.

Examples 231 to 244

According to the method of Example 129 and Example 230 Step 2, the compounds of Examples 231 to 244 shown below were synthesized. In the case of separating the diastereomers, the first eluted compound was designated as A and the later eluted compound as B. The ratio of diastereomers is 1:1 mixture unless otherwise specified. The necessary raw materials are listed in the following table.

TABLE 12-1 Example Starting Material ArSO2Cl Name of the Synthesized Compound 231 Reference Example F5

4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1- hydroxyethyl)benzenesulfonamide (diastereomer mixture) 232 Reference Reference 5-chloro-4-hydroxy-N-((1S,2R)-2-(8-methylnaphthalene-1-yl)-1- Example F4 Example E7 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8- sulfonamide (diastereomer mixture) 233 Reference Reference 5-chloro-N-((1S,2R)-2-(2-fluoronaphthalene-1-yl)-1-(5-oxo 4,5- Example F3 Example E7 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8- sulfonamide (diastereomer mixture) 234A Reference Reference 5-chloro-N-((1S,2R)-2-(2-fluoronaphthalene-1-yl)-1-(5-oxo-4,5- Example F3 Example E7 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8- sulfonamide 235A Reference Reference 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 235-B Example F1 Example E7 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8- sulfonamide 236 Reference Reference 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example F1 Example E19 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-(1- hydroxyethyl)benzenesulfonamide (diastereomer mixture) 237A Reference Reference N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example F1 Example E23 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-2,2- dimethylchroman-8-sulfonamide 238A Reference Reference 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5- Example F7 Example E7 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4- hydroxychroman-8-sulfonamide 239A Reference Reference 5-chloro-N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5- Example F9 Example E7 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4- hydroxychroman-8-sulfonamide

TABLE 12-2 Starting Example Material ArSO2Cl Name of the Synthesized Compound 240 Reference Reference 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example F1 Example E25 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-8-hydroxy-5,6,7,8- tetrahydronaphthalene-1-sulfonamide (diastereomer mixture) 241 Reference Reference 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example F1 Example E8 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8- sulfonamide (diastereomer mixture) 242 Reference Reference 5,7-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- Example F1 Example E30 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4- hydroxychroman-8-sulfonamide (diastereomer mixture) 243A Reference Reference N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- 243-B Example F8 Example E7 dihydro-l,3,4-oxadiazol-2-yl)propyl)-5-chloro-4- hydroxychroman-8-sulfonamide 244A Reference Reference N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- 244-B Example F1 Example E9 dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-5- (tifluoromethyl)chroman-8-sulfonamide

Example 245 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinamide Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (100 mg) obtained from Reference Example D1 and methyl 5-chloro-2-(chlorosulfonyl)nicotinate (140 mg) obtained from Reference Example Ell, according to the method of Example 1 Steps 1, 2, methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate (174 mg) was obtained.

Step 2

Methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate (174 mg) obtained from the above Step 1 was dissolved in THF (2.5 mL) and water (2.5 mL), lithium hydroxide (30 mg) was added, and the reaction solution was stirred at 50° C. for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiiazol-2-yl)propyl)sulfamoyl)nicotinic acid (145 mg).

Step 3

To a toluene (1.2 mL) solution of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinic acid (10 mg) obtained from the above Step 2, DMF (30 μL) and thionyl chloride (60 μL) were sequentially added, and the reaction solution was stirred at 95° C. for 40 minutes. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The THF (2.0 mL) solution of the residue was slowly added dropwise to 28% aqueous ammonia solution (1.0 mL) at −10° C., and the reaction solution was stirred at room temperature for 30 min. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 246 to 264

Compounds of Examples 246 to 264 shown below were synthesized according to the procedures of Example 1 Steps 1 and 2, and Example 245 Step 2 and 3. The necessary raw materials are listed in the following table.

TABLE 13-1 Starting Example Material ArSO2Cl Amine Name of the Synthesized Compound 246 Reference Example D1

5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N,N-dimethylbenzamide 247 Reference Example D1

2-(azetidine-1-carbonyl)-4-chloro-N-((1S,2R)-2-(6-fluoro- 2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)benzenesulfonamide 248 Reference Example D1

5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N-(2-hydroxyethyl)benzamide 249 Reference Reference NH₃ 5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2- Example D4 Example E11 methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)nicotinamide 250 Reference Reference NH₃ 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- Example D1 Example E73 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)nicotinamide 251 Reference Reference MeNH2 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- Example D1 Example E73 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N-methylnicotinamide 252 Reference Reference MeNH2 3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E10 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N-methylpicolinamide 253 Reference Example D1 Reference Example E10

3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N,N-dimethylpicolinamide

TABLE 13-2 Starting Example Material ArSO2Cl Amine Name of the Synthesized Compound 254 Reference Reference NH₃ 5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2- Example D4 Example E73 methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)nicotinamide 255 Reference Reference NH₃ 5-chloro-4-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3- Example D1 Example E28 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide 256 Reference Example D1

NH₃ 3,5-dichloro-2-(N-((1S,2R)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide 257 Reference Reference NH₃ 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E12 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-4-methylbenzamide 258 Reference Reference NH₃ 5-chloro-3-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3- Example D1 Example E29 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide 259 Reference Reference NH₃ 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E14 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-4-methoxybenzamide 260 Reference Reference NH₃ 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example D1 Example E31 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4,5- dimethoxybenzamide 261 Reference Reference NH₃ 7-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- Example D1 Example E17 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2,3- dihydrobenzo[b][1,4]dioxin-6-carboxamide

TABLE 13-3 Starting Example Material ArSO2Cl Amine Name of the Synthesized Compound 262 Reference Reference NH₃ 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- Example D1 Example E53 (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-4-nitrobenzamide 263 Reference Reference NH₃ 4-(2,2-difluoroethoxy)-2-(N-((1S,2R)-2-(6-fluoro-2,3- Example D1 Example E47 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide 264 Reference Reference NH₃ 2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5- Example D5 Example E11 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5- chloronicotinamide

Example 265 4-amino-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide Step 1

Using (2S,3R)-2-amino-3-(2-fluoronaphthalen-1-yl)butanoic acid (45 mg) obtained in Reference Example D3 and 2-methoxy-4-nitrobenzene-1-sulfonyl chloride (60 mg), according to the method of Example 1, Steps 1 and 2, N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxy-4-nitrobenzenesulfonamide (32 mg) was obtained.

Step 2

N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxy-4-nitrobenzenesulfonamide (32 mg) obtained from the above Step 1 was dissolved in ethanol (2.0 mL) and water (1.0 mL), iron (30 mg) and ammonium chloride (20 mg) were sequentially added, and the reaction solution was stirred at 80° C. for 1 hour. The reaction solution was filtered through CELITE, and the residue was washed with ethyl acetate (10 mL). The combined filtrates were concentrated and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 266 to 272

Compounds of Examples 266 to 272 shown below were synthesized according to the method of Example 1 Steps 1 and 2 and Example 265 Step 2. The necessary raw materials are listed in the following table.

TABLE 14 Example Starting Material ArSO2Cl Name of the Synthesized Compound 266 Reference Example D21

4-amino-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)- 2-(5,6,7,8-tetrahydronaphthalen-1- yl)propyl)benzenesulfonamide 267 Reference Example D10

4-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methylbenzenesulfonamide 268 Reference Example D10

5-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)quinoline-8-sulfonamide 269 Reference Example D13

4-amino-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide 270 Reference Example D10

4-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 271 Reference Example D1

2-amino-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide 272 Reference Reference methyl 4-amino-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3- Example D1 Example E53 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzoate

Example 273 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (50 mg) obtained in Reference Example D1 and 4-(2-(benzyloxy)ethyl)-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonyl chloride (142 mg) obtained in Reference Example E65, according to the method of Example 1 Steps 1 and 2, 4-(2-(benzyloxy)ethyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (22 mg) was obtained.

Step 2

To a THF (1.5 mL) solution of 4-(2-(benzyloxy)ethyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (20 mg) obtained from the above Step 1, 20 wt % palladium hydroxide (30 mg) was added, and the reaction mixture was stirred at room temperature for 30 minutes under hydrogen atmosphere. The reaction solution was filtered through CELITE, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound.

Example 274 N-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetamide

To a dichloromethane (1.0 mL) solution of 2-Amino-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (5.0 mg) obtained from Example 271, Pyridine (5.0 μL) and acetic anhydride (4.0 μL) were sequentially added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was added to hydrochloric acid (1 M, 5.0 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 275 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide Step 1

From 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (14.3 mg) obtained in Reference Example F1 and tert-butyl 5-chloro-8-(chlorosulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate (25.3 mg) obtained in Reference Example E58, according to the method of Example 129, tert-butyl 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (30.4 mg) was obtained.

Step 2

To tert-butyl 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b] [1,4]oxazin-4(3H)-carboxylate (30.4 mg) obtained from the above Step 1, hydrochloric acid-1, 4-dioxane (4 M, 5.0 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain the title compound.

Examples 276 to 283

Compounds of Examples 276 to 283 shown below were synthesized according to the method of Example 129 and Example 275 Step 2. The necessary raw materials are listed in the following table.

TABLE 15 Starting Example Material ArSO2Cl Name of the Synthesized Compound 276 Reference Reference methyl 6-amino-3-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- Example D10 Example E56 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2-methoxybenzoate 277 Reference Reference 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example D1 Example E52 dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N-methylbenzamide 278 Reference Reference 4-amino-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- Example D1 Example E70 dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8-sulfonamide 279 Reference Reference 2-(1-aminocyclopropyl)-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- Example D1 Example E55 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide 280 Reference Reference N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- Example D1 Example E59 oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide 281 Reference Reference N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- Example D1 Example E24 oxadiazol-2-yl)propyl)-1,2,3,4-tetrahydroisoquinoline-5-sulfonamide 282 Reference Reference N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- Example D1 Example E51 oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide 283 Reference Reference 6-(3-aminopyrrolidine-1-carbonyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3- Example D1 Example E41 dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine- 2-sulfonamide

Example 284 4-acetyl-5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

To a dichloromethane (1.0 mL) solution of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (31.5 mg) obtained in Example 275, triethylamine (40 μL) and acetic anhydride (20 μL) were sequentially added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain the title compound.

Example 285 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N-hydroxybenzamide Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (125 mg) obtained in Reference Example D1 and tert-butylbenzyloxy (5-chloro-2-(chlorosulfonyl)benzoyl)carbamate (280 mg) obtained in Reference Example E51 as a starting material, according to the method of Example 1 Step 1, (2S,3R)-2-(2-((benzyloxy)(tert-butoxycarbonyl)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (250 mg) was synthesized.

Step 2

(2S,3R)-2-(2-((benzyloxy)(tert-butoxycarbonyl)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (250 mg) obtained in the above Step 1 was dissolved in hydrochloric acid-1,4-dioxane (4 M, 4 mL), and the reaction solution was stirred at 45° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to give (2S,3R)-2-(2-((benzyloxy)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (215 mg).

Step 3

From (2S,3R)-2-(2-((benzyloxy)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (215 mg) obtained from the above Step 2, according to the method of Example 1 Step 2, N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (75 mg) was given.

Step 4

To a methanol (4.0 mL) solution of N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (75 mg) obtained from the above Step 3, 10% palladium-carbon (55 mg) was added, and the reaction solution was stirred under a hydrogen atmosphere for 1.5 hours. Insoluble matter was removed by CELITE filtration, and the residue was washed with methanol (10 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 286 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N-hydroxybenzamide

To dichloromethane (3.0 mL) solution of N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (66 mg) obtained from Example 285 Step 3, boron tribromide (1.0 M, 170 μL) was added at −60° C., and the reaction solution was stirred at 0° C. for 1 hour. Methanol (1.0 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain the title compound.

Example 287 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzothioamide

To a toluene (500 μL) solution of 5-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl)sulfamoyl)benzamide (15 mg) obtained in Example 5, Lawesson's reagent (20 mg) was added at room temperature, and the reaction solution was stirred at 100° C. for 12 hours. After allowing to cool to room temperature and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound.

Example 288 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

To a methanol (1.0 mL) solution of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (48 mg) obtained in Example 275, acetic acid (20 μL) and aqueous 37% formaldehyde solution (30 μL) were added successively, and the reaction solution was stirred at room temperature for 30 minutes. Sodium borohydride (12 mg) was added to the reaction solution, and the mixture was further stirred for 20 minutes. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Example 289 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide Step 1

From 5-((1S,2R)-1-amino-2-(3-chloro-6-fluoro-2-methylphenyl)propyl)-1,3,4-oxadiazol-2 (3H)-one monohydrochloride (10.3 mg) obtained in Reference Example F7 and tert-butyl 5-chloro-8-(chlorosulfonyl)-2H-benzo[b][1,4]oxazin-4 (3H)-carboxylate (25.3 mg) obtained from Reference Example E58, according to the method of Example 129, tert-butyl 5-chloro-8-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate (25.4 mg) was obtained.

Step 2

To tert-butyl 5-chloro-8-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4 (3H)-carboxylate (25.4 mg) obtained from the above Step 1, hydrochloric acid-1,4-dioxane (4 M, 5.0 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (15.2 mg).

Step 3

From 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b] [1,4]oxazine-8-sulfonamide (15.2 mg) obtained from the above Step 2, according to the method of Example 288, the title compound was synthesized.

Example 290 4-chloro-N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-2-hydroxy-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide Step 1

Using (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-hydroxypropionic acid (139 mg) obtained from Reference Example D56 and 4-chloro-2-methoxybenzenesulfonyl chloride (175 mg), according to the method of Example 1 Step 1, (2S)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)-3-hydroxypropionic acid (163 mg) was synthesized.

Step 2

To a DMF (10 mL) solution of (2S)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)-3-hydroxypropionic acid (163 mg) obtained from the above Step 1, Imidazole (753 mg) and tert-butyldimethylchlorosilane (563 mg) were sequentially added, and the reaction solution was stirred at 60° C. for 12 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate/hexane=1/1 (30 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and THF (2.0 mL), potassium carbonate (1.0 g) and water (2.0 mL) were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was added to hydrochloric acid (1 M, 20 mL) and extracted with ethyl acetate/hexane=1/1 (30 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain (2S)-3-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)propionic acid (175 mg).

Step 3

From (2S)-3-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)propionic acid (175 mg) obtained from the above Step 2, according to the method of Example 1 Step 2, N-((1S)-2-((tert-butyldimethylsilyl)oxy)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-4-chloro-2-methoxybenzenesulfonamide (126 mg) was obtained.

Step 4

To a THF (6.0 mL) solution of N-((1S)-2-((tert-butyldimethylsilyl)oxy)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-4-chloro-2-methoxybenzenesulfonamide (126 mg) obtained in the above Step 3, acetic acid (600 μL) and tetra-n-butylammonium fluoride (6.0 mL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate/hexane=1/1 (30 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound as a diastereomeric mixture.

Example 291 4-chloro-N-((1R)-2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide

To a dichloromethane (200 μL) solution of 4-chloro-N-((1 S)-2-(6-fluoro-2,3-dimethylphenyl)-2-hydroxy-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide (5.6 mg) obtained from Example 290, DAST (10 μL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (10 mL). The organic layer was washed with saturated saline (5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile) to obtain the title compound as a diastereomeric mixture.

Example 292 5-chloro-4-fluoro-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8-sulfonamide

From 5-chloro-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide (13 mg) obtained in Example 233, according to the method of Example 291, the title compound was obtained as a 1:1 diastereomeric mixture.

Example 293 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2,2,2-trifluoroacetyl)pyridine-2-sulfonamide

From 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-sulfonamide (15.6 mg) obtained in Example 221, according to the method of Reference Example E46 Step 1, the title compound was obtained.

Example 294 3-acetyl-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

From 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-methoxybenzenesulfonamide obtained in Example 204, the title compound was obtained according to the method of Reference Example E46 Step 1.

Example 295 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2H-chromene-8-sulfonamide Step 1

From (2S,3R)-2-amino-3-(2,3-dimethylphenyl)butanoic acid (58 mg) obtained in Reference Example D6 and 5-chloro-4-oxochroman-8-sulfonyl chloride (88 mg) obtained in Reference Example E7, in accordance with the procedures of Example 1 Steps 1 and 2, 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (63.4 mg) was obtained.

Step 2

From 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (63.4 mg) obtained from the Step 1 above, according to the method of Example 230 Step 2, 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide (48 mg) was obtained as a diastereomeric mixture.

Step 3

To a toluene (2.0 mL) solution of 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide (10 mg) obtained from the above Step 2, p-toluenesulfonic acid monohydrate (2.0 mg) was added, and the reaction solution was stirred at 110° C. for 30 minutes. The reaction solution was added to water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 296 4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4 oxadiazol-2-yl)propyl)-2-(hydroxymethyl)benzenesulfonamide Step 1

Using (2S,3R)-2-amino-3-(2,3-dihydro-1H-inden-4-yl)butanoic acid (50 mg) obtained from Reference Example D10 and methyl 5-chloro-2-(chlorosulfonyl)benzoate (71 mg), according to the method of steps 1 and 2 of Example 1, methyl 5-chloro-2-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (43 mg) was obtained.

Step 2

To a THF (2.0 mL) solution of methyl 5-chloro-2-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (15 mg) obtained in the above Step 1, a THF solution of lithium borohydride (2 M, 100 μL) was added, and the reaction solution was stirred at 60° C. for 1 hour. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 297 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxy-3-(1-(methoxymethoxy)ethyl)benzenesulfonamide

To a toluene (1.5 mL) solution of 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-methoxybenzenesulfonamide (10 mg) obtained from Example 204, N, N-diisopropylethylamine (25 μL) and chloromethyl methyl ether (10 μL) were sequentially added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound.

Example 298 4-chloro-N-((1S,2R)-2-(4-fluoro-4′-methoxy-2-methyl-[1,1′-biphenyl]-3-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide Step 1

Using (2S,3R)-2-amino-3-(3-bromo-6-fluoro-2-methylphenyl)butanoic acid (200 mg) obtained in Reference Example D5 and 4-chloro-2-methoxybenzenesulfonyl chloride (280 mg), according to the method of steps 1 and 2 of Example 1, N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (262 mg) was synthesized.

Step 2

To a 1,4-dioxane (1.0 mL) solution of N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (11 mg), 4-methoxyphenylboronic acid (5.0 mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (4.0 mg), and a sodium carbonate aqueous solution (2 M, 100 μL) was added sequentially at room temperature, and the reaction solution was stirred at 100° C. for 1 hour. The reaction solution was allowed to cool to room temperature, insoluble matter was removed by CELITE filtration, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Examples 299-324

Using N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide obtained from Example 298 Step 1, according to the method of Example 298, Step 2, compounds of Examples 299 to 324 shown below were synthesized. The boronic acids or boronic acid esters used are listed in the following table.

TABLE 16-1 Example Reagent ArSO2Cl 299

4-chloro-2-methoxy-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2- (3′,4,5′-trifluoro-2-methyl-[1,1′-biphenyl]-3-yl)propyl)benzenesulfonamide 300

4-chloro-N-((1S5,2R)-2-(6-fluoro-2-methyl-3-(pyridin-3-yl)phenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 301

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1H-pyrazol-3-yl)phenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 302

4-chloro-N-((1S,2R)-2-(4′-chloro-4-fluoro-2-methyl-[1,1-biphenyl]-3-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 303

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1H-pyrazol-4-yl)phenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 304

4-chloro-N-((1S,2R)-2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 305

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1-methyl-1H-pyrazol-3-yl)phenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 306

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 307

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 308

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(3-methyl-1H-pyrazol-4-yl)phenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

TABLE 16-2 Example Reagent ArSO2Cl 309

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(2-phenyloxazol-5-yl)phenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 310

4-chloro-N-((1S,2R)-2-(3-(1-ethyl-1H-pyrazol-4-yl)-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 311

4-chloro-N-((1S,2R)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 312

4-chloro-N-((1S,2R)-2-(3-(1-cyclobutyl-1H-pyrazol-4-yl)-6-fluoro-2-methylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 313

4-chloro-N-((1S,2R)-2-(3-(6-chloropyridin-3-yl)-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 314

4-chloro-N-((1S,2R)-2-(6-fluoro-3-(6-methoxypyridin-3-yl)-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 315

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(6-morpholinopyridin-3-yl)phenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 316

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(3-(tifluoromethyl)-1H-pyrazol-4- yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 317

4-chloro-N-((1S,2R)-2-(3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 318

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(pyrimidin-5-yl)phenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide 319

4-chloro-N-((1S,2R)-2-(6-fluoro-3-(2-methoxypyrimidin-5-yl)-2-methylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

TABLE 16-3 Example Reagent ArSO2Cl 320

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(6-(piperidin-1-yl)pyridin-3- yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 321

4-chloro-N-((1S,2R)-2-(3-(5-chloro-6-methoxypyridin-3-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 322

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(4-methyl-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine-7-yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 323

4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(5-(morpholine-4-carbonyl)pyridin-3- yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide 324

5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide

Example 325 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide Step 1

From (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethyl phenyl)butanoic acid (200 mg) obtained from Reference Example D1 and 3-bromo-4-chlorobenzenesulfonyl chloride (306 mg), according to the method of Steps 1 and 2 of Example 1, 3-bromo-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (274 mg) was synthesized.

Step 2

To a 1,4-dioxane (0.7 ml) solution of 3-bromo-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (5.6 mg) obtained from the above Step 1, (1-methyl-1H-pyrazol-4-yl)boronic acid (6.2 mg), [1,1′-bis(diphenylphosphino)ferrocene] palladium (II) dichloride dichloromethane adduct (5.0 mg), a sodium carbonate aqueous solution (2 M, 100 μL) were added sequentially at room temperature, and the reaction solution was stirred for 4 hours at 100° C. The reaction solution was allowed to cool to room temperature, insoluble matter was removed by CELITE filtration, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Example 326 6-chloro-2′-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-[1,1′-biphenyl]-3-sulfonamide

Using 3-bromo-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide obtained from Example 325 Step 1 and (2-fluorophenyl)boronic acid, the title compound was synthesized according to the method of Example 325 Step 2.

Example 327 4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(phenylethynyl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

To a DMF (1.0 mL) solution of N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (10.9 mg) obtained from Example 298 Step 1, dichlorobis (triphenylphosphine) palladium (11) (1.5 mg), copper (I) iodide (1.5 mg), triethylamine (30 μL) and ethynylbenzene (20 μL) were sequentially added at room temperature, the reaction solution was added at 100° C., and the mixture was stirred for 4 hours. The reaction solution was allowed to cool to room temperature, and insoluble matter was removed by CELITE filtration, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Example 328 4-amino-5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methylchroman-8-sulfonamide

To a benzene (1.5 ml) solution of 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8-sulfonamide (17 mg) obtained from Example 209A, trimethylsilylazide (50 μL), boron trifluoride-dimethylethercomplex (100 μL) were sequentially added, and the reaction solution was stirred for 1 hour at room temperature. To the reaction solution, a saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate/hexane=1/1 (10 mL). The organic layer was washed with saturated saline (10 mL), dried with anhydride sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in THF (1.5 ml) and water (50 μL). Triphenylphosphine (15 mg) was added to the residue, and the reaction solution was stirred for 2 hours at room temperature. Insoluble matter was removed by CELITE filtration, and the residue was washed with ethyl acetate/hexane=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound as a 1:1 diastereomeric mixture.

Example 329 4-amino-N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-methyl-chroman-8-sulfonamide

The title compound was prepared using N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) propyl)-5-chloro-4-hydroxy-4-methylchroman-8-sulfonamide obtained in Example 222A according to the method of example 328.

Example 330 4-amino-5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3, 4-oxadiazol-2-yl)propyl)-4-methyl chroman-8-sulfonamide Isomer A and Isomer B

To a 1,4-dioxane solution (1.0 mL) of a diastereomeric mixture of 4-amino-5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methylchroman-8-sulfonamide (6.4 mg) obtained in Example 328, triethylamine (100 μL) and di-tert-butyl dicarbonate (54 mg) were added at room temperature, and the reaction solution was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was purified by reverse phase HPLC (water/acetonitrile), and the fractions were concentrated to give each of two diastereomeric products. The substance eluted first was designated Compound A, and the substance eluted later was designated as Compound B. The obtained Compounds A and B were each dissolved in hydrochloric acid-dioxane (4 M, 2.0 mL), and the reaction solution was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. The substance obtained from compound A was designated as compound 330A, and the substance obtained from compound B as compound 330B.

Example 331 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(1,3,4-oxadiazol-2-yl)benzamide Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (80 mg) obtained in Reference Example D1 and ethyl 3-(chlorosulfonyl)-4-cyanobenzoate (146 mg) obtained in Reference Example E13, according to the method of steps 1 and 2 of Example 1, ethyl 4-cyano-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (40 mg) was obtained.

Step 2

To a DMSO (1 mL) solution of ethyl 4-cyano-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (40 mg) obtained from the above Step 1, 30% hydrogen peroxide water (0.5 ml) and potassium carbonate (20 mg) were added, and the reaction solution was stirred at 70° C. for 1 hour. 1M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to give 4-carbamoyl-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid (8.9 mg).

Step 3

To a dichloromethane (1.5 mL) solution of 4-carbamoyl-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid (16 mg) obtained from the above Step 2, (isocyanoimino) triphenylphosphorane (36 mg) was added thereto, and the reaction solution was stirred at room temperature for 72 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain the title compound (1.1 mg).

Example 332 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide Step 1

(2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (300 mg) obtained from Reference Example D1 was dissolved in water (5.0 mL) and 1,4-dioxane (5.0 mL), triethylamine (570 μL) was added, and it was cooled to 0° C. 4-Bromo-2-cyanobenzene-1-sulfonyl chloride (362 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 45 minutes. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to give (2S,3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (465 mg).

Step 2

To a THF (1.5 mL) solution of (2S,3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (22 mg) obtained from the above Step 1, CDI (13 mg) was added, the reaction solution was stirred at room temperature for 30 minutes, then hydrazine⋅monohydrate (12 μL) was added and the mixture was stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethanol (1.2 mL), carbon disulfide (10 μL) and potassium hydroxide (10 mg) were sequentially added, and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 333 to 335

According to the method of Example 332 steps 1 and 2, the compounds of Examples 333 to 335 shown below were synthesized. The raw materials are listed in the following table.

TABLE 17 Example Starting Material ArSO2Cl Name of the Synthesized Compound 333 Reference Example D10

methyl 2,6-dichloro-3-(N-((1S/2R)-2- (2,3-dihydro-1H-inden-4-yl-1-(5- thioxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)propyl)-sulfamoyl)benzoate 334 Reference Example D10

methyl 2-chloro-5-(N-((1S,2R)-2- (2,3-dihydro-1H-inden-4-yl)-1-(5- thioxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)-propyl)sulfamoyl)benzoate 335 Reference Example D26

4-bromo-N-((1S,2R)-2-(5,5-dimethyl- 5,6,7,8-tetrahydronaphthalen-1-yl)-1-(5- thioxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)propyl)benzenesulfonamide

Example 336 4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1

Using (2S,3R)-2-amino-3-(2,3-dihydro-1H-inden-4-yl)butanoic acid (20 mg) and 3-acetyl-4-chlorobenzene-1-sulfonyl chloride (20 mg) obtained in Reference Example D10, according to the method of Example 332 steps 1 and 2, 3-acetyl-4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (12 mg) was obtained.

Step 2

From 3-acetyl-4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (12 mg) obtained from the above Step 1, the title compound was obtained according to the method of Example 186 Step 2.

Example 337 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4 oxadiazol-2-yl)propyl)-N-methylsulfamoyl)benzamide Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (530 mg) obtained from Reference Example D1 and 4-chloro-2-cyanobenzene-1-sulfonyl chloride (660 mg), according to the method of Example 1 Step 1, (2S,3R)-2-(4-chloro-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (777 mg) was obtained.

Step 2

To a THF (500 μL) solution of (2S,3R)-2-(4-chloro-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (11 mg) obtained from the above Step 1, CDI (15 mg) was added, and the reaction solution was stirred for 1 hour at room temperature. Methanol (1.0 mL) was added to the reaction solution, and the mixture was further stirred for 16 hours. The reaction solution was added to water (10 mL) and extracted with diethyl ether (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl (2S,3R)-2-(4-chloro-2-cyanophenyl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (12 mg).

Step 3

To methyl (2S,3R)-2-(4-chloro-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (100 mg) obtained from the above Step 2, Methanol (2 mL), dichloromethane (2 mL), and a hexane solution of trimethylsilyl diazomethane (0.6 M, 800 μL) were sequentially added, and the reaction solution was stirred at room temperature for 1 hour. By concentrating the reaction solution under reduced pressure, methyl (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (101 mg) was obtained.

Step 4

Methyl (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (101 mg) obtained from the Step 3 above, according to the method of Example 245 Step 2, (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (8.5 mg) was obtained.

Step 5

To (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamide)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (8.5 mg) obtained from the above Step 4, according to the method of Example 1 Step 2, 4-chloro-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-N-methylbenzenesulfonamide (6.0 mg) was obtained.

Step 6

From 4-chloro-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-N-methylbenzenesulfonamide (6.0 mg) obtained from the above Step 5, according to the method of Example 1 Step 3, the title compound was obtained.

Example 344 6-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4′-methoxy-[1,1′-biphenyl]-3-sulfonamide

Using 3-bromo-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide and (4-methoxyphenyl)boronic acid obtained from Example 325 step 1, the title compound was synthesized according to the method of Example 325 Step 2.

Example 345 3-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2′-methoxy-[1,1′-biphenyl]-4-carboxamide Step 1

From (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid obtained from Reference Example D1 and 5-bromo-2-cyanobenzenesulfonyl chloride, according to the method of steps 1 and 2 of Example 1, 5-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide was synthesized.

Step 2

Using 5-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide obtained from the above Step 1 and 2-methoxyphenylboronic acid, according to the method of Example 325 Step 2 and Example 1 Step 3, the title compound was obtained.

Example 346 4-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2 yl)propyl)sulfamoyl)-3-methoxybenzamide

From 4-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide obtained in Example 342, the title compound was obtained according to the method of Example 1 Step 3.

Example 347 4-(N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2 yl)propyl)sulfamoyl)benzamide

From 4-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide obtained in Example 341, according to the method of Example 1 Step 3, the title compound was obtained.

Example 348 4-bromo-N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)benzenesulfonamide Step 1

Using (2S,3R)-2-amino-3-(naphthalen-1-yl)butanoic acid obtained in Reference Example D11 and 4-bromobenzenesulfonyl chloride, according to the method of Step 1 of Example 1, (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanoic acid was obtained.

Step 2

To a DMF (2.5 ml) solution of (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanoic acid (283 mg) obtained from the above Step 1, ammonium chloride (41 mg), HOBt (103 mg), triethylamine (0.264 ml) and WSC (146 mg) were added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanamide as a crude product.

Step 3

To a DMF (2 ml) solution of (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanamide obtained from the above Step 2, cyanuric chloride (59 mg) was added at 0° C., and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added to water and extracted with a mixed solvent of ethyl acetate/toluene. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give 4-bromo-N-((1S,2R)-1-cyano-2-(naphthalen-1-yl)propyl)benzene sulfonamide (137 mg).

Step 4

To an ethanol (2 ml) solution of 4-bromo-N-((1S,2R)-1-cyano-2-(naphthalen-1-yl)propyl)benzenesulfonamide (137 mg) obtained from the above Step 3, water (0.66 ml) and a 50% aqueous solution of hydroxylamine (0.060 ml) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2S,3R)-2-((4-bromophenyl)sulfonamido)-N-hydroxy-(3-naphthalen-1-yl)butanamide (130 mg) as a crude product.

Step 5

To a DMF (1.0 ml) solution of (2S,3R)-2-((4-bromophenyl)sulfonamido)-N-hydroxy-3-(naphthalen-1-yl)butanamide (20 mg) obtained from the above Step 4, Pyridine (0.004 ml) and 2-ethylhexyl chloroformate (0.009 ml) were added, and the reaction solution was stirred at room temperature for 1 hour. Further, xylene was added, and the reaction solution was stirred overnight at 100° C. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate/hexane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound (37 mg).

Example 349 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-2-methoxybenzenesulfonamide Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid obtained in Reference Example D1 and 4-chloro-2-methoxybenzenesulfonyl chloride, according to the method of Example 1 Step 1, (2S,3R)-2-((4-chloro-2-methoxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid was obtained.

Step 2

From (2S,3R)-2-((4-chloro-2-methoxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid obtained from the above Step 1, the titled compound was obtained according to the method of Example 348 Step 2 to Step 5.

Example 350

(2S,3R)-2-((4-chloro-2-methoxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (142 mg) obtained from Example 348 Step 1 was dissolved in a DMF (3.3 mL), and WSC (130 mg), HOBt (100 mg), N, N-diisopropylethylamine (200 μL) and thiosemicarbazide (70 mg) were sequentially added, and the reaction solution was stirred at 80° C. for 4 hours. The reaction solution was added to a saturated aqueous solution of ammonium chloride (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate). The obtained residue was dissolved in ethanol (1.5 mL), a 20% aqueous sodium hydroxide solution (2.0 mL) was added, and the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was added to hydrochloric acid (1 M, 5.0 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Comparative Example 1

According to the method described in Non-Patent Document 11, a compound of the following formula was obtained.

¹H NMR (CD3OD) δ: 7.54 (d, J=8.4 Hz, 2H), 7.17-7.29 (m, 5H), 7.08-7.14 (m, 2H), 4.55-4.61 (m, 1H), 3.00-3.13 (m, 2H), 2.39 (s, 3H)

Hereinafter, the structural formulas and physical properties of Example Compounds 1 to 350 are shown.

TABLE 18-1 Example Structural Formula Physical Property Value 1

1H NMR (CD3OD) δ: 7.74-7.78 (m, 3H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.78-4.81 (m, 1H), 3.51-3.61 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 525, 527 2

1H NMR (CD3OD) δ: 8.20 (1H, d, J = 8.1 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.03-7.00 (1H, m), 6.98-6.96 (2H, m), 4.63-4.61 (1H, m), 3.40-3.36 (1H, m), 2.91-2.82 (4H, m), 2.03-1.99 (2H, m), 1.41 (3H, d, J = 7.0 Hz); LC/MS RT 1.66 min, m/z [M − H]⁻ 476, 478 3

1H NMR (CD3OD) δ: 7.77 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H), 7.03 (dd, J = 7.0, 2.2 Hz, 1H), 6.90-6.99 (m, 2H), 4.53 (d, J = 9.5 Hz, 1H), 3.52- 3.61 (m, 1H), 2.20 (s, 3H), 2.18 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.63 min, m/z [M − H]⁻ 463, 465 4

1H NMR (CD3OD) δ: 7.74 (s, 1H), 7.67-7.69 (m, 2H), 7.01- 7.07 (m, J = 6.2 Hz, 1H), 6.91- 6.99 (m, 2H), 4.54 (d, J = 9.5 Hz, 1H), 3.51-3.65 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 507, 509 5

1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (dd, J = 8.2, 5.7 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.82 (d, J = 11.4 Hz, 1H), 3.50-3.60 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 481, 483

TABLE 18-2 Example Structural Formula Physical Property Value 6

1H NMR (CD3OD) δ: 8.11 (d, J = 8.8 Hz, 1H), 7.76-7.89 (m, 3H), 7.62 (d, J = 2.2 Hz, 1H), 7.51-7.59 (m, 2H), 7.40-7.47 (m, 1H), 7.22 (dd, J = 11.5, 9.0 Hz, 1H), 4.90-4.98 (m, 1H), 4.09-4.18 (m, 1H), 1.60 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 503, 505 7

1H NMR (CD3OD) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H), 6.80 (dd, J = 10.4, 2.7 Hz, 1H), 6.69 (dd, J = 9.2, 2.7 Hz, 1H), 4.55 (d, J = 8.8 Hz, 1H), 3.53-3.65 (m, 1H), 2.21 (s, 3H), 2.15 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 481, 483 8

1H NMR (CD3OD) δ: 7.62- 7.79 (m, 2H), 7.46-7.52 (m, 2H), 7.38-7.45 (m, 2H), 7.29- 7.35 (m, 1H), 7.20-7.28 (m, 2H), 4.82-4.86 (m, 1H), 4.44- 4.62 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]⁻ 503, 505 9

1H NMR (CD3OD) δ: 8.01- 8.11 (m, 1H), 7.75-7.85 (m, 1H), 7.43-7.59 (m, 4H), 7.22- 7.38 (m, 3H), 4.78 (d, J = 7.3 Hz, 1H), 4.20 (t, J = 7.0 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 503, 505 10

1H-NMR (CDCl3) δ: 7.85 (1H, d, J = 7.7 Hz), 7.67 (1H, s), 7.36-7.33 (1H, m), 6.92-6.88 (2H, m), 6.69 (1H, dd, J = 11.7, 8.4 Hz), 6.00 (1H, s), 5.87 (1H, s), 4.89 (1H, t, J = 10.1 Hz), 3.45 (1H, s), 2.42 (3H, s), 2.17- 2.15 (6H, m), 1.44 (3H, d, J = 6.6 Hz); LC/MS RT 1.59 min, m/z [M − H]⁻ 461

TABLE 18-3 Example Structural Formula Physical Property Value 11

1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.75 (dd, J = 11.7, 8.8 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 3.50-3.60 (m, 1H), 2.52-2.59 (m, 2H), 2.24 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H),; LC/MS RT 1.73 min, m/z [M − H]⁻ 495, 497 12

1H NMR (CD3OD) δ: 8.10 (br d, J = 8.8 Hz, 1H), 7.76- 7.84 (m, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.39-7.45 (m, 2H), 7.33 (d, J = 8.1 Hz, 1H), 7.21 (dd, J = 11.4, 9.2 Hz, 1H), 4.91 (d, J = 11.7 Hz, 1H), 4.07- 4.21 (m, 1H), 2.39 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 483 13

1H NMR (CD3OD) δ: 7.86 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.57-7.61 (m, 1H), 6.91 (dd, J = 11.0, 8.4 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 3.55-3.66 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]⁻ 499, 501 14

1H NMR (CD3OD) δ: 7.86 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 8.4, 2.2 Hz, 1H), 7.25 (dd, J = 8.8, 5.1 Hz, 1H), 6.88 (t, J = 10.0 Hz, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.55-3.65 (m, 1H), 2.37 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]⁻ 501, 503 15

1H NMR (CD3OD) δ: 8.11 (d, J = 8.8 Hz, 1H), 7.69-7.92 (m, 5H), 7.54 (br t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.21 (dd, J = 11.4, 9.2 Hz, 1H), 4.89-5.01 (m, 1H), 4.10-4.24 (m, 1H), 1.60 (br d, J = 6.6 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]⁻ 547, 549

TABLE 18-4 Example Structural Formula Physical Property Value 16

1H NMR (CD3OD) δ: 7.69 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.2, 2.0 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 12.1, 8.4 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 3.46-3.60 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.95-2.04 (m, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.06 (dd, J = 8.4, 1.8 Hz, 2H), 0.72- 0.90 (m, 2H); LC/MS RT 1.67 min, m/z [M − H]⁻ 487 17

1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.53- 7.66 (m, 2H), 7.12-7.22 (m, 1H), 6.89-7.03 (m, 1H), 4.71-4.82 (m, 1H), 3.86- 4.04 (m, 1H), 2.28 (s, 3H), 1.47 (br d, J = 6.2 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 501, 503 18

1H NMR (CD3OD) δ: 7.74 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.37 (dd, J = 8.2, 1.6 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 3.47-3.63 (m, 1H), 2.71 (q, J = 7.7 Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H), 1.21-1.28 (m, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 475 19

1H NMR (CD3OD) δ: 8.32 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 12.1, 8.4 Hz, 1H), 4.84 (d, J = 11.4 Hz, 1H), 3.55-3.68 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 482, 484 20

1H NMR (CD3OD) δ: 7.87 (d, J = 7.6 Hz, 1H), 7.53- 7.70 (m, 3H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.50- 3.52 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.54 min, m/z [M − H]⁻ 447

TABLE 18-5 Example Structural Formula Physical Property Value 21

1H NMR (CD3OD) δ: 7.76 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.52-7.55 (m, 1H), 6.96-7.05 (m, 2H), 6.83 (s, 1H), 4.59 (d, J = 9.5 Hz, 1H), 3.37-3.44 (m, 1H), 2.22 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.60 min, m/z [M − H]⁻ 467, 469 22

LC/MS RT 1.6 min, m/z [M − H]⁻ 467, 469 23

1H NMR (CD3OD) δ: 7.73 (d, J = 8.4 Hz, 1H), 7.52- 7.59 (m, 2H), 7.07 (td, J = 7.9, 5.5 Hz, 1H), 6.90-6.97 (m, 1H), 6.66-6.77 (m, 1H), 4.77 (d, J = 11.4 Hz, 1H), 3.43-3.59 (m, 1H), 2.38 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]⁻ 467, 469 24

1H NMR (cdcl3) δ: 7.73 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.00-7.16 (m, 4H), 4.56 (dd, J = 15.8, 7.7 Hz, 1H), 3.37-3.62 (m, 1H), 2.29 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]⁻ 449, 451 25

1H NMR (CD3OD) δ: 7.74- 7.79 (m, 3H), 7.25 (dd, J = 8.9, 5.0 Hz, 1H), 6.85-6.94 (m, 1H), 4.77-4.83 (m, 1H), 3.55-3.65 (m, 1H), 2.37 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]⁻ 545, 547

TABLE 18-6 Example Structural Formula Physical Property Value 26

1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 6.94 (dd, J = 8.5, 5.9 Hz, 1H), 6.73 (dd, J = 11.9, 8.5 Hz, 1H), 4.77 (d, J = 11.4 Hz, 1H), 3.50-3.65 (m, 1H), 2.39 (s, 3H), 1.73-1.83 (m, 1H), 1.46 (d, J = 7.0 Hz, 3H), 0.80-0.98 (m, 2H), 0.37-0.55 (m, 2H); LC/MS RT 1.76 min, m/z [M − H]⁻ 507, 509 27

1H-NMR (CDCl3) δ: 8.26 (1H, br s), 7.94 (1H, d, J = 8.1 Hz), 7.55-7.47 (3H, m), 6.90 (2H, t, J = 9.7 Hz), 6.19-6.14 (1H, m), 4.90 (1H, t, J = 10.1 Hz), 3.56 (1H, br s), 2.39 (3H, s), 1.48 (3H, d, J = 7.0 Hz), 1.24 (1H, s).; LC/MS RT 1.73 min, m/z [M − H]⁻ 535, 537 28

1H NMR (CD3OD) δ: 7.86 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.4, 2.2 Hz, 1H), 6.83-6.95 (m, 2H), 4.78 (d, J = 11.0 Hz, 1H), 3.45-3.56 (m, 1H), 2.20 (d, J = 2.2 Hz, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.60 min, m/z [M − H]⁻ 485, 487 29

1H-NMR (CDCl3) δ: 8.88 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.24-7.21 (1H, m), 7.03-7.01 (1H, m), 6.94- 6.93 (1H, m), 6.84 (1H, dd, J = 11.4, 8.4 Hz), 6.02-5.95 (2H, m), 5.89 (1H, s), 4.80 (1H, t, J = 10.8 Hz), 3.93 (3H, s), 3.46 (1H, s), 2.35 (3H, s), 1.49 (3H, d, J = 5.9 Hz).; LC/MS RT 1.38 min, m/z [M − H]⁻ 497, 499 30

1H NMR (CD3OD) δ: 7.85 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.57-7.61 (m, 1H), 7.44 (dd, J = 8.8, 5.1 Hz, 1H), 6.80-6.86 (m, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.55-3.65 (m, 1H), 2.43 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]⁻ 545, 547

TABLE 18-7 Example Structural Formula Physical Property Value 31

1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 8.6, 5.3 Hz, 1H), 6.65- 6.80 (m, 1H), 4.83-4.91 (m, 1H), 3.55-3.65 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.3 Hz, 3H); LC/MS RT 1.52 min, m/z [M − H]⁻ 482, 484 32

1H NMR (CD3OD) δ: 7.67 (1H, d, J = 8.8 Hz), 7.54- 7.52 (2H, m), 6.95-6.92 (1H, m), 6.59-6.53 (1H, m), 4.79 (1H, d, J = 11.0 Hz), 3.56- 3.54 (1H, m), 2.24 (3H, s), 2.19 (3H, s), 1.15 (3H, d, J = 7.0 Hz); LC/MS RT 1.66 min, m/z [M − H]⁻ 481, 483 33

1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.53- 7.70 (m, 2H), 6.98 (dd, J = 8.2, 5.7 Hz, 1H), 6.72 (dd, J = 12.1, 8.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 3.48- 3.61 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 481, 483 34

1H NMR (CD3OD) δ: 7.68 (dd, J = 7.9, 0.9 Hz, 1H), 7.51-7.58 (m, 2H), 6.94 (dd, J = 8.2, 6.0 Hz, 1H), 6.52- 6.66 (m, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.51-3.68 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.16 (d, J = 6.6 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 481, 483 35

1H NMR (CD3OD) δ: 7.77 (s, 3H), 7.41-7.51 (m, 1H), 6.72-6.91 (m, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.52-3.73 (m, 1H), 2.43 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.73 min, m/z [M − H]⁻ 589, 591

TABLE 18-8 Example Structural Formula Physical Property Value 36

1H-NMR (CDCl3) δ: 9.73 (1H, br s), 7.87 (1H, s), 7.64-7.56 (2H, m), 7.06- 7.04 (1H, m), 6.91 (1H, dd, J = 8.2, 5.7 Hz), 6.70- 6.65 (2H, m), 6.47 (1H, s), 4.87 (1H, t, J = 10.6 Hz), 3.78-3.76 (4H, m), 3.64-3.62 (2H, m), 3.48- 3.46 (1H, m), 3.41-3.39 (2H, m), 2.16-2.14 (6H, m), 1.46 (3H, d, J = 6.6 Hz).; LC/MS RT 1.50 min, m/z [M − H]⁻ 560 37

1H-NMR (CDCl3) δ: 7.86 (1H, s), 7.65-7.55 (2H, m), 7.06-7.03 (1H, m), 6.93- 6.89 (1H, m), 6.71-6.66 (1H, m), 6.14 (1H, s), 6.03 (1H, s), 4.96 (1H, t, J = 10.3 Hz), 3.43-3.41 (1H, m), 3.11 (3H, s), 2.94 (3H, s), 2.15 (6H, s), 1.51 (3H, d, J = 7.0 Hz); LC/MS RT 1.51 min, m/z [M − H]⁻ 518 38

1H NMR (CD3OD) δ: 8.18 (1H, s), 7.67 (1H, s), 6.96 (1H, dd, J = 8.4, 5.9 Hz), 6.71 (1H, dd, J = 11.7, 8.4 Hz), 4.81 (1H, d, J = 11.0 Hz), 3.56 (1H, s), 3.33 (1H, s), 2.20 (3H, s), 2.16 (3H, s), 1.45 (3H, d, J = 6.6 Hz).; LC/MS RT 1.46 min, m/z [M − H]⁻ 525, 527 39

1H NMR (CD3OD) δ: 7.88 (1H, s), 7.72 (1H, s), 6.99- 6.94 (1H, m), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 4.77 (1H, d, J = 11.0 Hz), 3.58 (1H, s), 3.13 (3H, s), 2.90 (3H, s), 2.22 (3H, s), 2.17 (3H, s), 1.44-1.42 (3H, m); LC/MS RT 1.58 min, m/z [M − H]⁻ 552, 554 40

1H NMR (CD3OD) δ: 8.76 (s, 1H), 7.62 (s, 1H), 6.98 (dd, J = 8.2, 6.0 Hz, 1H), 6.73 (dd, J = 11.9, 8.6 Hz, 1H), 4.83-4.86 (m, 1H), 3.51-3.73 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 482, 484

TABLE 18-9 Example Structural Formula Physical Property Value 41

1H NMR (CD3OD) δ: 8.06 (d, J = 9.2 Hz, 1H), 7.87- 7.91 (m, 2H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.72 (dd, J = 11.7, 8.3 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 3.49- 3.66 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 515 42

1H NMR (CD3OD) δ: 8.08 (d, J = 8.1 Hz, 1H), 7.88- 7.94 (m, 2H), 7.44 (dd, J = 8.8, 5.1 Hz, 1H), 6.82 (dd, J = 11.4, 8.8 Hz, 1H), 4.79- 4.85 (m, 1H), 3.56-3.71 (m, 1H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]⁻ 579, 581 43

1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.55- 7.65 (m, 2H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.54 (br d, J = 11.4 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H); LC/MS RT 1.64 min, m/z [M − H]⁻ 484, 486 44

1H NMR (CD3OD) δ: 8.01 (d, J = 8.4 Hz, 1H), 7.78- 7.86 (m, 1H), 7.71 (dd, J = 8.6, 2.0 Hz, 1H), 7.50 (s, 4H), 7.37-7.47 (m, 3H), 7.09-7.25 (m, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.05-4.23 (m, 1H), 1.54 (d, J = 6.6 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 486, 488 45

1H NMR (CD3OD) δ: 7.76- 7.85 (m, 1H), 7.65-7.74 (m, 2H), 7.54 (s, 2H), 7.51 (d, J = 5.5 Hz, 1H), 7.34 (d, J = 5.5 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.14-7.23 (m, 1H), 4.67 (d, J = 9.5 Hz, 1H), 3.44-3.58 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]⁻ 492, 494

TABLE 18-10 Example Structural Formula Physical Property Value 46

LC/MS RT 1.89 min, m/z [M − H]⁻ 476, 478 47

1H NMR (CD3OD) δ: 7.83 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.08 (dd, J = 8.1, 1.8 Hz, 1H), 6.90- 7.00 (m, 2H), 6.83 (d, J = 7.0 Hz, 1H), 4.29 (d, J = 10.6 Hz, 1H), 3.54-3.63 (m, 1H), 2.59-2.83 (m, 4H), 1.90-1.98 (m, 1H), 1.61-1.82 (m, 4H), 1.37 (d, J = 7.0 Hz, 3H), 1.03- 1.12 (m, 2H), 0.76-0.87 (m, 2H); LC/MS RT 1.97 min, m/z [M − H]⁻ 486 48

1H NMR (CD3OD) δ: 8.58-8.67 (m, 1H), 8.08- 8.34 (m, 1H), 7.78-7.96 (m, 1H), 6.89-7.18 (m, 3H), 4.72 (d, J = 10.3 Hz, 0.5H), 4.41 (d, J = 11.0 Hz, 0.5H), 3.36-3.50 (m, 2H), 2.93-3.10 (m, 1H), 2.70 (dt, J = 15.9, 8.2 Hz, 1H), 1.98-2.27 (m, 1H), 1.67-1.85 (m, 1H), 1.46 (d, J = 6.6 Hz, 1.5H), 1.35 (d, J = 6.6 Hz, 1.5H), 1.15 (d, J = 7.0 Hz, 1.5H), 1.10 (d, J = 7.0 Hz, 1.5H); LC/MS RT 1.79 min, m/z [M − H]⁻ 491, 493 49

1H NMR (CD3OD) δ: 8.53 (dd, J = 2.2, 0.7 Hz, 1H), 8.11 (dd, J = 8.2, 2.4 Hz, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.26-7.41 (m, 4H), 7.16 (d, J = 7.7 Hz, 1H), 4.68 (d, J = 9.9 Hz, 1H), 3.87 (s, 2H), 3.49-3.61 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.83 min, m/z [M − H]⁻ 525, 527 50

1H NMR (CD3OD) δ: 8.44 (d, J = 2.2 Hz, 1H), 8.02-8.09 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.09- 7.46 (m, 5H), 4.83-4.85 (m, 1H), 4.30-4.442 (m, 1H), 3.65 (s, 2H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 525, 527

TABLE 18-11 Example Structural Formula Physical Property Value 51

1H NMR (CD3OD) δ: 8.07- 8.19 (m, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 3H), 7.63-7.70 (m, 1H), 7.47- 7.54 (m, 1H), 7.34-7.45 (m, 3H), 4.63 (d, J = 8.1 Hz, 1H), 4.06-4.21 (m, 1H), 1.54 (d, J = 7.0 Hz, 3H); LC/MS RT 1.73 min, m/z [M − H]⁻ 453 52

1H NMR (CD3OD) δ: 8.52 (d, J = 2.6 Hz, 1H), 8.01 (dd, J = 8.4, 2.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 4.8 Hz, 2H), 6.83-6.91 (m, 1H), 4.50 (d, J = 10.3 Hz, 1H), 3.51-3.61 (m, 1H), 2.55- 2.96 (m, 4H), 1.54-1.91 (m, 4H), 1.36 (d, J = 6.6 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]⁻ 447, 449 53

1H NMR (CD3OD) δ: 7.94 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8.4, 2.2 Hz, 1H), 6.99-7.02 (m, 1H), 6.91-6.97 (m, 1H), 6.84 (d, J = 7.3 Hz, 1H), 4.54 (d, J = 9.5 Hz, 1H), 3.58-3.69 (m, 4H), 2.63-2.85 (m, 4H), 1.64-1.88 (m, 4H), 1.32 (d, J = 6.6 Hz, 3H); LC/MS RT 1.92 min, m/z [M − H]⁻ 520, 522 54

LC/MS RT 1.94 min, m/z [M − H]⁻ 491, 493 55

1H NMR (CD3OD) δ: 7.66 (d, J = 8.7 Hz, 1H), 6.93-7.00 (m, 2H), 6.83 (d, J = 7.0 Hz, 1H), 6.51-6.56 (m, 2H), 4.25 (d, J = 11.0 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.47-3.61 (m, 1H), 2.60-2.79 (m, 4H), 1.59-1.85 (m, 4H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]⁻ 472

TABLE 18-12 Example Structural Formula Physical Property Value 56

1H NMR (CD3OD) δ: 8.13 (dd, J = 9.5, 5.5 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.37-7.53 (m, 3H), 7.30 (td, J = 8.8, 2.6 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.4, 1.8 Hz, 1H), 4.48 (d, J = 10.3 Hz, 1H), 4.11-4.21 (m, 1H), 3.94 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]⁻ 490, 492 57

1H NMR (CD3OD) δ: 8.00 (d, J = 8.4 Hz, 1H), 7.83- 7.91 (m, 2H), 6.91-7.02 (m, 2H), 6.78-6.86 (m, 1H), 4.36 (d, J = 10.6 Hz, 1H), 4.05 (s, 3H), 3.53-3.63 (m, 1H), 2.59-2.87 (m, 4H), 1.62-1.87 (m, 4H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.83 min, m/z [M − H]⁻ 487, 489 58

1H NMR (CD3OD) δ: 8.28- 8.34 (m, 1H), 6.92-7.00 (m, 2H), 6.80-6.89 (m, 1H), 4.43 (d, J = 10.6 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.47-3.60 (m, 1H), 2.60- 2.85 (m, 4H), 1.60-1.87 (m, 4H), 1.33 (d, J = 6.6 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]⁻ 506 59

1H NMR (CD3OD) δ: 8.12-8.30 (m, 2H), 7.74 (dd, J = 8.8, 7.3 Hz, 1H), 6.72-7.02 (m, 3H), 4.52 (d, J = 10.3 Hz, 1H), 3.30- 3.40 (m, 1H), 2.68-2.92 (m, 4H), 1.88-2.01 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]⁻ 456 60

1H NMR (cdcl3) δ: 7.60 (t, J = 8.1 Hz, 1H), 7.31- 7.37 (m, 1H), 7.20-7.26 (m, 1H), 7.06-7.10 (m, 1H), 7.01-7.06 (m, 1H), 6.88 (d, J = 7.3 Hz, 1H), 5.46 (br s, 1H), 4.52 (br t, J = 7.9 Hz, 1H), 3.29-3.41 (m, 1H), 2.70-2.90 (m, 4H), 1.95-2.07 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.87 min, m/z [M − H]⁻ 494, 496

TABLE 18-13 Example Structural Formula Physical Property Value 61

1H NMR (cdcl3) δ: 7.62-7.69 (m, 1H), 7.52-7.59 (m, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.03 (s, 2H), 6.86-6.92 (m, 1H), 5.46 (br s, 1H), 4.54 (br t, J = 8.1 Hz, 1H), 3.30-3.46 (m, 1H), 2.72-2.91 (m, 4H), 1.96-2.09 (m, 2H), 1.37-1.42 (m, 1H), 1.40 (d, J = 7.0 Hz, 2H); LC/MS RT 1.82 min, m/z [M − H]⁻ 450, 452 62

1H NMR (CD3OD) δ: 7.79-7.87 (m, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.27-7.36 (m, 2H), 7.07 (d, J = 1.8 Hz, 1H), 6.95 (dd, J = 8.4, 2.2 Hz, 1H), 4.46 (d, J = 9.9 Hz, 1H), 3.93 (s, 3H), 3.70-3.78 (m, 1H), 1.59 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]⁻ 478, 480 63

1H NMR (CD3OD) δ: 9.16 (1H, s), 7.91-7.88 (1H, m), 7.66 (1H, d, J = 8.4 Hz), 7.39-7.31 (2H, m), 7.07-7.07 (1H, m), 6.99-6.97 (1H, m), 3.95 (3H, s), 3.49-3.48 (1H, m), 3.15- 3.13 (1H, m), 1.66 (3H, d, J = 7.0 Hz); LC/MS RT 1.62 min, m/z [M − H]⁻ 479, 481 64

1H NMR (CD3OD) δ: 7.70 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.08-7.11 (m, 1H), 6.99-7.04 (m, 1H), 6.80 (d, J = 7.0 Hz, 1H), 6.61-6.73 (m, 1H), 4.55 (d, J = 10.6 Hz, 1H), 4.44- 4.51 (m, 2H), 3.94 (s, 3H), 3.19-3.28 (m, 1H), 3.09 (t, J = 8.6 Hz, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]⁻ 464, 466 65

1H NMR (CD3OD) δ: 8.07- 8.21 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.44-7.53 (m, 1H), 7.31- 7.42 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.96-7.06 (m, 1H), 5.16 (d, J = 11.7 Hz, 1H), 4.07-4.15 (m, 1H), 3.95 (s, 3H), 2.49 (s, 3H), 1.77 (d, J = 7.3 Hz, 2.3H), 1.66 (d, J = 7.3 Hz, 0.7H); LC/MS RT 1.82 min, m/z [M − H]⁻ 486, 488

TABLE 18-14 Example Structural Formula Physical Property Value 66

1H NMR (CD3OD) δ: 7.67- 7.77 (m, 1H), 7.10-7.15 (m, 1H), 7.01-7.05 (m, 1H), 6.97- 7.01 (m, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 4.36-4.56 (m, 2H), 4.30 (d, J = 11.4 Hz, 1H), 3.94 (s, 3H), 3.21-3.29 (m, 1H), 3.13 (t, J = 8.6 Hz, 2H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]⁻ 464, 466 67

1H NMR (CD3OD) δ: 7.71 (dd, J = 8.4, 0.7 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 2H), 6.91-6.99 (m, 2H), 4.29 (dd, J = 11.2, 1.6 Hz, 1H), 3.94 (s, 3H), 3.30-3.36 (m, 1H), 2.91-3.16 (m, 2H), 2.28-2.55 (m, 3H), 1.44 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 6.4 Hz, 1.5H), 1.0 (d, J = 6.4 Hz, 1.5H); LC/MS RT 1.89 min, m/z [M − H]⁻ 476, 478 68

1H NMR (CD3OD) δ: 8.62 (d, J = 8.8 Hz, 1H), 8.19 (dd, J = 7.3, 1.1 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.64-7.71 (m, 1H), 7.56-7.62 (m, 1H), 7.48- 7.56 (m, 1H), 6.92 (d, J = 4.8 Hz, 2H), 6.83 (d, J = 4.4 Hz, 1H), 4.20 (d, J = 10.6 Hz, 1H), 3.20-3.30 (m, 1H), 2.68- 2.83 (m, 4H), 1.83-1.89 (m, 2H), 1.33 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 448 69

LC/MS RT 1.86 min, m/z [M − H]⁻ 476, 478 70

1H NMR (CD3OD) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.26-7.43 (m, 3H), 7.09-7.21 (m, 5H), 7.04 (dd, J = 8.4, 1.8 Hz, 1H), 6.96 (dd, J = 7.1, 1.6 Hz, 1H), 4.37 (d, J = 10.6 Hz, 1H), 3.95 (s, 3H), 3.61-3.68 (m, 1H), 2.13 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.93 min, m/z [M − H]⁻ 512, 514

TABLE 18-15 Example Structural Formula Physical Property Value 71

1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.59-7.62 (m, 1H), 7.46 (d, J = 6.2 Hz, 1H), 7.31-7.37 (m, 1H), 7.21-7.29 (m, 2H), 7.06 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 8.4, 1.8 Hz, 1H), 4.61-4.74 (m, 1H), 4.37 (d, J = 10.6 Hz, 1H), 3.90 (s, 3H), 2.96 (s, 3H), 1.67 (d, J = 7.0 Hz, 3H); LC/MS RT 1.81 min, m/z [M − H]⁻ 486, 488 72

1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.01-7.09 (m, 2H), 6.71 (d, J = 7.7 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 4.28-4.33 (m, 1H), 4.23 (d, J = 11.0 Hz, 1H), 4.07-4.15 (m, 1H), 3.94 (s, 3H), 3.41- 3.50 (m, 1H), 3.33-3.39 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]⁻ 478, 480 73

1H NMR (CD3OD) δ: 7.76 (d, J = 8.4 Hz, 1H), 7.10- 7.14 (m, 1H), 6.97-7.09 (m, 2H), 6.62-6.67 (m, 1H), 6.51-6.62 (m, 1H), 4.50-4.57 (m, 1H), 4.38-4.48 (m, 1H), 4.11-4.16 (m, 1H), 3.94 (s, 3H), 3.33-3.46 (m, 2H), 1.41 (d, J = 7.0 Hz, 3H), 1.20- 1.24 (m, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 478, 480 74

1H NMR (CD3OD) δ: 7.71 (d, J = 8.4 Hz, 1H), 6.98- 7.17 (m, 5H), 4.54 (d, J = 11.0 Hz, 0.34H), (d, J = 11.0 Hz, 0.68H), 3.95 (s, 1H), 3.85 (s, 2H), 3.48-3.59 (m, 1H), 1.51 (d, J = 7.0 Hz, 2H), 1.17 (d, J = 7.0 Hz, 1H),; LC/MS RT 1.67 min, m/z [M − H]⁻ 458, 460 75

1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.08- 7014 (m, 2H), 6.95-7.06 (m, 1H), 6.95-7.06 (m, 1H), 6.84 (t, J = 9.0 Hz, 1H), 4.34 (d, J = 11.0 Hz, 1H), 3.94 (s, 3H), 3.52-3.63 (m, 1H), 2.17 (d, J = 2.2 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]⁻ 454, 456

TABLE 18-16 Example Structural Formula Physical Property Value 76

LC/MS RT 1.78 min, m/z [M − H]⁻ 490, 492 77

1H NMR (CD3OD) δ: 7.71 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.94-7.06 (m, 2H), 6.73-6.86 (m, 1H), 4.30 (d, J = 10.6 Hz, 1H), 3.94 (s, 3H), 3.54-3.64 (m, 1H), 2.20 (s, 3H), 2.10 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]⁻ 468, 470 78

1H NMR (CD3OD) δ: 7.68 (d, J = 7.3 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.28-7.37 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.09-7.15 (m, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 8.4, 1.8 Hz, 1H), 4.39 (dd, J = 9.0, 6.4 Hz, 1H), 3.89-3.99 (m, 1H), 3.88 (s, 3H), 3.62- 3.69 (m, 1H), 2.89 (s, 3H); LC/MS RT 1.80 min, m/z [M − H]⁻ 472, 474 79

1H NMR (CD3OD) δ: 7.73 (d, J = 8.4 Hz, 0.5H), 7.66 (d, J = 8.4 Hz, 0.5H), 6.98- 7.17 (m, 3H), 6.75 (t, J = 9.3 Hz, 1H), 4.66 (d, J = 11.0 Hz, 0.5H), 4.57 (d, J = 11.4 Hz, 0.5H), 3.95 (s, 1.5H), 3.82 (s, 1.5H), 3.61- 3.78 (m, 1H), 2.15 (s, 3H), 1.52 (d, J = 7.0 Hz, 1.5H), 1.15 (d, J = 7.0 Hz, 1.5H); LC/MS RT 1.76 min, m/z [M − H]⁻ 472, 474 80

1H NMR (CD3OD) δ: 7.61- 7.80 (m, 1H), 6.76-7.19 (m, 5H), 4.55 (d, J = 11.0 Hz, 0.33H), 4.40 (d, J = 11.0 Hz, 0.67H), 3.94 (s, 2H), 3.80 (s, 1H), 3.39-3.49 (m, 1H), 2.15-2.20 (m, 3H), 1.48 (d, J = 7.0 Hz, 2H), 1.14 (d, J = 7.0 Hz, 1H); LC/MS RT 1.73, 1.76 min, m/z [M − H]⁻ 454, 456

TABLE 18-17 Example Structural Formula Physical Property Value 81

1H NMR (CD3OD) δ: 7.80 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.43- 7.50 (m, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.22-7.29 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 4.64-4.76 (m, 1H), 4.36-4.49 (m, 3H), 2.96 (s, 3H), 2.47-2.58 (m, 2H), 1.68 (d, J = 7.0 Hz, 3H); LC/MS RT 1.88 min, m/z [M − H]⁻ 548, 550 82

1H NMR (DMSO-d6) δ: 11.63 (br s, 1H), 7.31 (br dd, J = 8.1 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.46- 7.62 (m, J = 8.4 Hz, 4H), 7.30 (dd, J = 10.4, 7.9 Hz, 1H), 7.10-7.26 (m, 2H), 7.01 (dd, J = 8.6, 1.6 Hz, 1H), 4.33-4.50 (m, 1H), 4.06-4.22 (m, 1H), 3.86 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 490, 492 83

1H NMR (CD3OD) δ: 7.74 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.03-7.07 (m, 1H), 6.96 (dd, J = 8.2, 5.7 Hz, 1H), 6.69 (dd, J = 11.7, 8.4 Hz, 1H), 4.68 (br d, J = 11.0 Hz, 1H), 3.95 (s, 3H), 3.61-3.68 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]⁻ 468, 470 84

1H NMR (CD3OD) δ: 7.87 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.4, 1.8 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.52-3.63 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]⁻ 463, 465 85

1H NMR (CD3OD) δ: 7.73 (d, J = 8.1 Hz, 1H), 7.08-7.16 (m, 1H), 6.89- 7.07 (m, 4H), 4.40 (d, J = 10.3 Hz, 1H), 3.95 (s, 3H), 3.71-3.83 (m, 1H), 3.45- 3.58 (m, 1H), 2.33 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.24 (d, J = 7.3 Hz, 6H); LC/MS RT 1.88 min, m/z [M − H]⁻ 478, 480

TABLE 18-18 Example Structural Formula Physical Property Value 86

1H NMR (CD3OD) δ: 7.73 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.92-7.05 (m, 4H), 4.35 (d, J = 11.0 Hz, 1H), 3.95 (s, 3H), 3.52-3.62 (m, 1H), 2.55-2.78 (m, 2H), 2.24 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H), 1.08 (t, J = 7.3 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 464, 466 87

1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.98-7.06 (m, 3H), 6.94 (d, J = 2.2 Hz, 1H), 4.29 (d, J = 10.6 Hz, 1H), 3.94 (s, 3H), 3.58-3.63 (m, 1H), 2.51-2.66 (m, 2H), 2.21 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.08 (t, J = 7.5 Hz, 3H); LC/MS RT 1.84 min, m/z [M − H]⁻ 464, 466 88

1H NMR (CD3OD) δ: 7.88 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.87-7.06 (m, 1H), 6.67- 6.77 (m, 1H), 4.70-4.78 (m, 3H), 3.63-3.71 (m, 1H), 2.84-2.95 (m, 2H), 2.22 (s, 3H), 2.17 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]⁻ 508, 510 89

1H NMR (CD3OD) δ: 7.74 (d, J = 8.4 Hz, 1H), 7.10-7.27 (m, 2H), 7.04 (dd, J = 8.4, 1.8 Hz, 1H), 4.64-4.75 (m, 1H), 4.06- 4.22 (m, 1H), 3.96 (s, 3H), 2.32 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.84 min, m/z [M − H]⁻ 550, 552 90

1H NMR (CD3OD) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.4, 1.8 Hz, 1H), 6.89 (dd, J = 9.8 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 3.95 (s, 3H), 3.63- 3.72 (m, 1H), 2.18 (s, 3H), 2.17 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]⁻ 486, 488

TABLE 18-19 Example Structural Formula Physical Property Value 91

1H NMR (CD3OD) δ: 8.51 (d, J = 1.8 Hz, 1H), 8.09-8.21 (m, 1H), 7.768-7.73 (m, 2H), 6.92-7.01 (m, 2H), 6.63-6.78 (m, 1H), 4.61-4.71 (m, 1H), 3.53-3.75 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 505, 507 92

LC/MS RT 1.79 min, m/z [M − H]⁻ 507, 509 93

1H NMR (CD3OD) δ: 7.45 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J = 8.4 Hz), 6.96 (1H, dd, J = 8.6, 5.9 Hz), 6.70 (1H, dd, J = 12.1, 8.6 Hz), 4.66- 4.80 (4H, m), 3.46 (3H, s), 2.19 (3H, s), 2.16 (3H, s), 1.49 (3H, d, J = 6.6 Hz); LC/MS RT 1.71 min, m/z [M − H]⁻ 523, 525 94

1H-NMR (CDCl3) δ: 7.77 (1H, s), 7.42 (1H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 8.3, 5.9 Hz), 6.69 (1H, dd, J = 11.5, 8.3 Hz), 5.43 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 4.34-4.29 (1H, m), 4.23-4.19 (1H, m), 3.41 (1H, br s), 3.10-3.07 (2H, m), 2.98-2.83 (2H, m), 2.18-2.17 (6H, m), 1.56-1.53 (3H, m), 1.27- 1.23 (3H, m).; LC/MS RT 1.85 min, m/z [M − H]⁻ 523, 525 95

1H-NMR (CDCl3) δ: 8.88 (1H, s), 7.68-7.64 (1H, m), 6.98-6.92 (2H, m), 6.73- 6.68 (1H, m), 5.48-5.43 (1H, m), 4.95-4.81 (1H, m), 4.55-4.49 (1H, m), 4.34- 4.20 (1H, m), 3.45 (1H, s), 2.92-2.82 (1H, m), 2.20- 2.18 (6H, m), 2.08 (2H, s), 2.02 (1H, s), 1.98-1.93 (1H, m), 1.86 (1H, s), 1.76 (2H, s), 1.57-1.51 (3H, m).; LC/MS RT 1.82, 1.87 min, m/z [M − H]⁻ 566, 568

TABLE 18-20 Example Structural Formula Physical Property Value 96

1H NMR (CD3OD) δ: 7.74- 7.78 (m, 3H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.75 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J =11.0 Hz, 1H), 3.51- 3.63 (m, 1H), 2.47-2.68 (m, 2H), 2.24 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H); LC/MS RT 1.75 min, m/z [M − H]⁻ 539, 541 97

1H-NMR (CDCl3) δ: 8.06- 7.99 (2H, m), 7.80 (1H, s), 7.07 (1H, t, J = 7.7 Hz), 6.93 (1H, dd, J = 8.5, 5.9 Hz), 6.69 (1H, dd, J = 11.5, 8.5 Hz), 5.28 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 3.46 (1H, br s), 2.92 (1H, d, J = 16.9 Hz), 2.69 (1H, d, J = 16.9 Hz), 2.20 (3H, s), 2.18 (3H, s), 1.64 (3H, s), 1.58-1.56 (3H, m), 1.46 (3H, s).; LC/MS RT 1.77 min, m/z [M − H]⁻ 502 98

LC/MS RT 1.66 min, m/z [M − H]⁻ 429 99

1H-NMR (CDCl3) δ: 8.11 (1H, br s), 7.66-7.63 (2H, m), 6.98-6.90 (2H, m), 6.71-6.66 (1H, m), 5.44 (1H, d, J = 10.5 Hz), 4.82 (1H, t, J = 10.5 Hz), 4.56- 4.52 (1H, m), 4.47-4.42 (1H, m), 4.01-3.95 (1H, m), 3.44-3.37 (1H, m), 2.17-2.16 (6H, m), 1.89 (1H, br s), 1.55 (3H, d, J = 7.0 Hz), 1.21-1.10 (2H, m), 0.92-0.89 (2H, m); LC/MS RT 1.69 min, m/z [M − H]⁻ 529 100

LC/MS RT 1.83, 1.90 min, m/z [M − H]⁻ 586, 588

TABLE 18-21 Example Structural Formula Physical Property Value 101

1H NMR (CD3OD) δ: 7.51 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.6 Hz), 6.97 (1H, dd, J = 8.2, 5.7 Hz), 6.71 (1H, dd, J = 11.9, 8.2 Hz), 6.04 (1H, tt, J = 55.5, 3.9 Hz), 4.82-4.58 (7H, m), 3.67-3.62 (1H, m), 2.19 (3H, s), 2.16 (3H, s), 1.47 (3H, d, J = 7.0 Hz); LC/MS RT 1.76 min, m/z [M − H]⁻ 573, 575 102

1H-NMR (CDCl3) δ: 7.67 (1H, br s), 7.46 (1H, d, J = 8.4 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.94 (1H, dd, J = 8.4, 5.5 Hz), 6.70 (1H, dd, J = 11.4, 8.4 Hz), 6.24 (1H, tt, J = 56.3, 4.5 Hz), 5.41 (1H, d, J = 10.5 Hz), 4.88 (1H, t, J = 10.5 Hz), 4.42-4.37 (1H, m), 4.29-4.25 (1H, m), 3.42 (1H, br s), 3.32- 3.17 (4H, m), 2.19-2.17 (6H, m), 1.55-1.54 (3H, m).; LC/MS RT 1.87 min, m/z [M − H]⁻ 559, 561 103

LC/MS RT 1.87 min, m/z [M − H]⁻ 496, 498 104

1H-NMR (CDCl3) δ: 8.21 (1H, br s), 7.79 (1H, d, J = 8.4 Hz), 7.49 (1H, dd, J = 8.6, 5.3 Hz), 7.04-7.01 (1H, m), 6.96-6.92 (2H, m), 5.60- 5.56 (1H, m), 4.79 (1H, t, J = 10.6 Hz), 3.95 (3H, s), 3.43 (1H, br s), 2.53 (3H, s), 1.55 (3H, d, J = 7.0 Hz).; LC/MS RT 1.64 min, m/z [M − H]⁻ 479, 481 105

LC/MS RT 1.71 min, m/z [M − H]⁻ 464, 466

TABLE 18-22 Example Structural Formula Physical Property Value 106

1H-NMR (CDCl3) δ: 7.92-7.86 (1H, m), 7.56-7.46 (1H, m), 7.08-7.00 (1H, m), 6.97-6.92 (1H, m), 6.73- 6.67 (1H, m), 5.52-5.45 (1H, m), 4.96-4.83 (1H, m), 4.61-4.37 (3H, m), 3.49 (1H, br s), 2.90-2.82 (1H, m), 2.54-2.48 (1H, m), 2.19-2.16 (6H, m), 2.09-2.09 (3H, m), 1.57- 1.50 (2H, m); LC/MS RT 1.81 1.85 min, m/z [M − H]⁻ 586 107

LC/MS RT 1.90 min, m/z [M − H]⁻ 506, 508 108

LC/MS RT 1.98 min, m/z [M − H]⁻ 568, 570 109

LC/MS RT 1.71 min, m/z [M − H]⁻ 497, 499 110

1H NMR (CD3OD) δ: 7.53-7.63 (m, 1H), 7.02-7.19 (m, 2H), 6.95- 7.01 (m, 1H), 6.72 (dd, J = 11.9, 8.6 Hz, 1H), 4.82-4.98 (m, 1H), 3.65-3.74 (m, 1H), 2.24 (s, 3H), 2.18 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]⁻ 440

TABLE 18-23 Example Structural Formula Physical Property Value 111

LC/MS RT 1.79 min, m/z [M − H]⁻ 474, 476 112

1H NMR (CD3OD) δ: 8.05 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.82 (d, J = 11.4 Hz, 1H), 3.99 (s, 3H), 3.66-3.76 (m, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]⁻ 469, 471 113

1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.6, 6.0 Hz, 1H), 6.73 (dd, J = 11.9, 8.6 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 3.75-3.83 (m, 4H), 3.63- 3.72 (m, 2H), 3.55-3.62 (m, 1H), 3.22-3.27 (m, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.47 (d, J = 7.3 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]⁻ 552, 554 114

1H NMR (CD3OD) δ: 8.17 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.4 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 3.58-3.66 (m, 3H), 3.21- 3.29 (m, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.94-2.01 (m, 4H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 536, 538 115

1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 7.93-8.02 (m, 1H), 6.99 (dd, J = 8.2, 6.0 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.94 (dd, J = 11.2, 3.1 Hz, 1H), 3.53-3.64 (m, 3H), 3.29- 3.36 (m, 2H), 3.23-3.29 (m, 2H), 2.21 (s, 3H), 2.18 (s, 3H), 1.92-2.08 (m, 6H), 1.46 (br d, J = 7.0 Hz, 3H); LC/MS RT 1.83 min, m/z [M − H]⁻ 576, 578

TABLE 18-24 Example Structural Formula Physical Property Value 116

1H NMR (CD3OD) δ: 8.16 (dd, J = 8.4, 5.1 Hz, 1H), 7.97 (dd, J = 11.7, 8.4 Hz, 1H), 6.96-7.02 (m, 1H), 6.73 (dd, J = 11.5, 8.4 Hz, 1H), 4.88-4.99 (m, 1H), 4.43- 4.50 (m, 1H), 4.21-4.28 (m, 2H), 3.56-3.64 (m, 1H), 3.37-3.49 (m, 1H), 3.16 (d, J = 12.8 Hz, 1H), 2.96 (d, J = 12.8 Hz, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.88-2.07 (m, 4H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 578, 580 117

1H NMR (CD3OD) δ: 8.17 (dd, J = 8.4, 2.6 Hz, 1H), 7.97 (dd, J = 8.4, 2.2 Hz, 1H), 6.99 (dd, J = 8.4, 5.7 Hz, 1H), 6.73 (dd, J = 11.5, 8.4 Hz, 1H), 4.91-4.97 (m, 1H), 4.66-4.73 (m, 1H), 3.80-3.90 (m, 2H), 3.54-3.77 (m, 4H), 2.19-2.22 (m, 3H), 2.18 (s, 3H), 2.03- 2.12 (m, 4H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]⁻ 578, 580 118

LC/MS RT 1.72 min, m/z [M − H]⁻ 497, 499 119

LC/MS RT 1.73 min, m/z [M − H]⁻ 541, 543 120

LC/MS RT 1.80 min, m/z [M − H]⁻ 555, 557

TABLE 18-25 Example Structural Formula Physical Property Value 121

LC/MS RT 1.93 min, m/z [M − H]⁻ 514, 516 122

LC/MS RT 1.91 min, m/z [M − H]⁻ 526, 528 123

1H-NMR (CDCl3) δ: 8.56 (0.5H, s), 8.04 (0.5H, s), 7.83-7.78 (1H, m), 7.07- 7.04 (1H, m), 6.96-6.93 (1H, m), 6.74-6.68 (1H, m), 5.43-5.40 (1H, m), 4.97- 4.91 (0.5H, m), 4.84-4.79 (0.5H, m), 4.60-4.42 (2H, m), 3.51 (1H, s), 2.94 (1H, s), 2.53-2.44 (1H, m), 2.22- 2.17 (9H, m), 1.57-1.50 (3H, m).; LC/MS RT 1.89, 1.94 min, m/z [M − H]⁻ 620, 622 124

1H NMR (CD3OD) δ: 7.88 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.8, 5.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 11.2, 9.0 Hz, 1H), 4.69- 4.80 (m, 3H), 3.63-3.79 (m, 1H), 2.85-2.92 (m, 2H), 2.44 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]⁻ 572, 574 125

1H-NMR (CDCl3) δ: 8.47 (1H, br s), 7.67 (1H, d, J = 8.4 Hz), 6.96-6.93 (2H, m), 6.82-6.82 (1H, m), 6.65 (1H, dd, J = 14.5, 8.2 Hz), 5.67 (1H, d, J = 9.6 Hz), 5.01 (1H, dd, J = 9.6, 1.6 Hz), 3.88 (3H, s), 2.29 (3H, s), 2.15 (3H, s), 1.66 (3H, d, J = 4.0 Hz), 1.58 (3H, d, J = 3.7 Hz).; LC/MS RT 1.87 min, m/z [M − H]⁻ 482, 484

TABLE 18-26 Example Structural Formula Physical Property Value 126

1H NMR (CD3OD) δ: 7.63 (1H, d, J = 8.4 Hz), 7.07 (1H, s), 6.98- 6.94 (2H, m), 6.70-6.66 (1H, m), 4.40 (1H, t, J = 7.7 Hz), 3.94 (3H, s), 3.26-3.23 (1H, m), 3.16-3.11 (1H, m), 2.17 (3H, s), 2.14 (3H, s); LC/MS RT 1.76 min, m/z [M − H]⁻ 454, 456 127

1H NMR (CD3OD) δ: 7.72 (1H, dd, J = 14.3, 8.4 Hz), 7.12-7.06 (1H, m), 7.05-6.99 (2H, m), 6.72-6.63 (1H, m), 4.34-4.16 (1H, m), 3.86-3.81 (3H, m), 2.37-2.30 (3H, m), 2.19 (3H, s), 1.57-1.54 (1H, m), 1.35-1.28 (1H, m), 0.93-0.87 (1H, m), 0.72-0.67 (1H, m); LC/MS RT 1.85 min, m/z [M − H]⁻ 480, 482 128

1H-NMR (CDCl3) δ: 7.84 (1H, br s), 7.78 (1H, d, J = 8.1 Hz), 7.00 (1H, dd, J = 8.4, 1.8 Hz), 6.95-6.91 (2H, m), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 5.46 (1H, d, J = 10.3 Hz), 4.82 (1H, t, J = 10.6 Hz), 3.94 (3H, s), 3.28-3.22 (1H, m), 2.27-2.25 (1H, m), 2.19-2.16 (6H, m), 1.96-1.87 (1H, m), 0.79 (3H, t, J = 7.3 Hz).; LC/MS RT 1.85 min, m/z [M − H]⁻ 482, 484 129

1H NMR (CD3OD) δ: 7.58- 7.73 (m, 1H), 6.91-7.11 (m, 2H), 6.62-6.81 (m, 1H), 4.71- 4.82 (m, 1H), 4.49-4.61 (m, 2H), 3.57-3.79 (m, 1H), 2.70- 2.95 (m, 1H), 2.28-2.38 (m, 0.5H), 2.20-2.25 (m, 3H), 2.16- 2.24 (m, 3H), 2.08-2.14 (m, 0.5H), 1.98-2.02 (m, 3H), 1.42- 1.56 (m, 3H); LC/MS RT 1.81, 1.87 min, m/z [M − H]⁻ 569, 571 130

1H NMR (CD3OD) δ: 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.39 (d, J = 2.6 Hz, 1H), 8.12-8.36 (m, 1H), 7.98 (dd, J = 8.2, 2.4 Hz, 1H), 7.69-7.86 (m, 1H), 7.55-7.68 (m, 2H), 7.42-7.51 (m, 2H), 5.21 (d, J = 7.7 Hz, 1H), 4.40-4.53 (m, 1H), 1.55 (d, J = 7.3 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 488, 490

TABLE 18-27 Example Structural Formula Physical Property Value 131

1H NMR (CD3OD) δ: 8.28 (dd, J = 6.2, 2.6 Hz, 1H), 8.08 (ddd, J = 8.7, 4.5, 2.6 Hz, 1H), 7.43-7.54 (m, 1H), 7.00-7.09 (m, 2H), 6.98 (d, J = 2.2 Hz, 1H), 4.42 (d, J = 10.6 Hz, 1H), 3.31-3.41 (m, 1H), 3.28 (s, 3H), 2.79-2.87 (m, 4H), 1.92-2.07 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 494 132

1H NMR (CD3OD) δ: 9.01 (dd, J = 4.2, 1.6 Hz, 1H), 8.28-8.45 (m, 2H), 8.15 (d, J = 7.0 Hz, 1H), 7.64-7.71 (m, 1H), 7.57-7.63 (m, 1H), 6.91- 7.00 (m, 2H), 6.85-6.91 (m, 1H), 4.45 (d, J = 10.6 Hz, 1H), 3.28-3.42 (m, 1H), 2.68-2.94 (m, 4H), 1.78- 2.08 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 449 133

1H NMR (CD3OD) δ: 8.88 (s, 1H), 8.59 (s, 1H), 8.01-8.08 (m, 1H), 7.56-7.65 (m, 1H), 7.45-7.54 (m, 1H), 7.36-7.42 (m, 1H), 6.98-7.06 (m, 2H), 6.85-6.93 (m, 1H); 4.23 (d, J = 11.0 Hz, 1H), 3.19-3.31 (m, 1H), 2.75-2.82 (m, 4H), 1.82-2.08 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]⁻ 465 134

1H NMR (cdcl3) δ: 7.81 (dd, J = 7.7, 1.8 Hz, 1H), 7.73 (br s, 1H), 7.43-7.50 (m, 1H), 7.03-7.07 (m, 2H), 7.00 (t, J = 7.7 Hz, 1H), 6.90-6.95 (m, 2H), 5.48 (d, J = 10.6 Hz, 1H), 4.47 (t, J = 10.3 Hz, 1H), 3.95 (s, 3H), 3.14-3.33 (m, 1H), 2.77-2.88 (m, 4H), 1.95-2.10 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]⁻ 428 135

1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.4, 2.2 Hz, 1H), 6.98-7.03 (m, 2H), 6.89-6.95 (m, 1H), 4.28 (d, J = 10.3 Hz, 1H), 3.25-3.33 (m, 1H), 2.88-3.11 (m, 2H), 2.75-2.85 (m, 4H), 1.84- 2.10 (m, 2H), 1.39 (d, J = 7.0 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H); LC/MS RT 2.02 min, m/z [M − H]⁻ 506, 508

TABLE 18-28 Example Structural Formula Physical Property Value 136

1H NMR (CD3OD) δ: 8.86 (d, J = 2.2 Hz, 1H), 8.24 (dd, J = 7.3, 1.5 Hz, 1H), 8.12 (s, 1H), 8.06 (dd, J = 8.1, 1.5 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 6.82-7.03 (m, 3H), 4.40 (d, J = 11.0 Hz, 1H), 3.32-3.40 (m, 1H), 2.70-2.89 (m, 4H), 2.54 (s, 3H), 1.79-2.13 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.79 min, m/z [M − H]⁻ 463 137

1H NMR (CD3OD) δ: 7.64 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.18 (dd, J = 8.4, 1.8 Hz, 1H), 6.97-7.07 (m, 2H), 6.90-6.96 (m, 1H), 4.30 (d, J = 11.0 Hz, 1H), 3.94 (s, 3H), 3.32- 3.38 (m, 1H), 2.78-2.89 (m, 4H), 1.90-2.11 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 506, 508 138

1H NMR (CD3OD) δ: 7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.59 (td, J = 8.0, 1.6 Hz, 1H), 7.26-7.33 (m, 3H), 6.99-7.05 (m, 2H), 6.92- 6.96 (m, 1H), 4.41 (d, J = 10.6 Hz, 1H), 3.36-3.42 (m, 1H), 2.78-2.91 (m, 4H), 1.91-2.04 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]⁻ 464 139

1H NMR (CD3OD) δ: 8.00 (d, J = 1.8 Hz, 1H), 7.94 (dd, J = 8.1, 1.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.99-7.07 (m, 2H), 6.94- 6.99 (m, 1H), 4.41 (d, J = 10.3 Hz, 1H), 3.56-3.60 (m, 2H), 3.39-3.46 (m, 2H), 3.25-3.29 (m, 1H), 2.78-2.87 (m, 4H), 1.93- 2.06 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.60 min, m/z [M − H]⁻ 488 140

1H NMR (CD3OD) δ: 7.39-7.43 (m, 1H), 7.36-3.38 (m, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.00-7.06 (m, 2H), 6.93-6.98 (m, 1H), 4.30 (d, J = 11.0 Hz, 1H), 3.30-3.35 (m, 1H), 2.74-2.87 (m, 8H), 1.91- 2.10 (m, 2H), 1.77-1.82 (m, 4H), 1.41 (d, J = 6.6 Hz, 3H); LC/MS RT 1.91 min, m/z [M − H]⁻ 452

TABLE 18-29 Example Structural Formula Physical Property Value 141

1H NMR (CD3OD) δ: 8.53- 8.55 (m, 1H), 8.23-8.31 (m, 1H), 8.10 (dd, J = 7.5, 2.0 Hz, 1H), 7.39-7.50 (m, 1H), 7.00-7.05 (m, 2H), 4.32 (d, J = 10.6 Hz, 1H), 4.03 (s, 3H), 3.45-3.52 (m, 1H), 2.76-2.93 (m, 4H), 1.93- 2.12 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 429 142

LC/MS RT 1.80 min, m/z [M − H]⁻ 519, 521 143

1H NMR (CD3OD) δ: 8.86-9.01 (m, 1H), 8.29- 8.55 (m, 1H), 7.95-8.24 (m, 1H), 7.37-7.52 (m, 1H), 6.63-7.24 (m, 4H), 4.26-4.46 (m, 1H), 3.14- 3.39 (m, 1H), 2.71-2.88 (m, 4H), 1.81-2.10 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]⁻ 494 144

LC/MS RT 1.92 min, m/z [M − H]⁻ 554, 556 145

LC/MS RT 1.86 min, m/z [M − H]⁻ 518, 520

TABLE 18-30 Example Structural Formula Physical Property Value 146

1H NMR (CD3OD) δ: 7.90 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 1.8 Hz, 1H), 7.33-7.35 (m, 1H), 6.88-7.05 (m, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 5.29- 5.43 (m, 1H), 4.74 (d, J = 11.4 Hz, 1H), 3.59-3.75 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.86 min, m/z [M − H]⁻ 504, 506 147

LC/MS RT 1.83 min, m/z [M − H]⁻ 480, 482 148

1H NMR (CD3OD) δ: 8.10 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.03 (s, 3H), 3.60-3.74 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]⁻ 469, 471 149

1H NMR (CD3OD) δ: 8.14-8.23 (m, 2H), 8.05-8.10 (m, 1H), 6.99 (dd, J = 8.4, 6.0 Hz, 1H), 6.75 (dd, J = 11.9, 8.4 Hz, 1H), 5.40 (d, J = 11.4 Hz, 1H), 3.65-3.77 (m, 1H), 2.23 (s, 3H), 2.20 (s, 3H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 522, 524 150

1H NMR (cdcl3) δ: 8.28-8.53 (m, 1H), 7.54 (br d, J = 8.1 Hz, 2H), 7.18 (br d, J = 8.1 Hz, 2H), 6.90-7.08 (m, 3H), 5.17 (br d, J = 9.2 Hz, 1H), 4.40 (t, J = 9.9 Hz, 1H), 3.49 (s, 2H), 3.44-3.61 (m, 1H), 2.38 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 400

TABLE 18-31 Example Structural Formula Physical Property Value 151

1H NMR (cdcl3) δ: 5.27 (d, J = 9.9 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.7 Hz, 4H), 6.94 (dd, J = 8.1, 5.9 Hz, 1H), 6.71 (dd, J = 11.4, 8.4 Hz, 1H), 5.27 (br d, J = 9.9 Hz, 1H), 4.79 (t, J = 10.3 Hz, 1H), 3.31-3.48 (m, 1H), 2.38 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 1.42 (br d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 418 152

1H-NMR (CDCl3) δ: 8.75 (1H, s), 7.72 (1H, d, J = 7.7 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.38-7.37 (1H, m), 7.22 (1H, t, J = 7.9 Hz), 6.91-6.86 (2H, m), 6.66-6.61 (1H, m), 5.48 (1H, d, J = 10.4 Hz), 4.74 (1H, t, J = 10.4 Hz), 3.34 (1H, br s), 2.12 (3H, s), 2.08 (3H, s), 1.36 (3H, d, J = 6.6 Hz); LC/MS RT 1.60 min, m/z [M − H]⁻ 443 153

1H NMR (CD3OD) δ: 9.09 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.70-7.76 (m, 1H), 6.91 (dd, J = 8.4, 5.9 Hz, 1H), 6.55-6.68 (m, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.62- 3.70 (m, 1H), 2.18 (s, 3H), 2.13 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]⁻ 489, 491 154

1H-NMR (CDCl3) δ: 8.63 (1H, s), 6.98-6.93 (1H, m), 6.92 (1H, s), 6.71 (1H, dd, J = 11.7, 8.4 Hz), 5.57 (1H, br s), 4.94-4.90 (1H, m), 4.03 (3H, s), 3.45 (1H, s), 2.18 (6H, s), 1.53 (3H, d, J = 7.0 Hz); LC/MS RT 1.65 min, m/z [M − H]⁻ 469, 471 155

1H-NMR (CDCl3) δ: 7.95-7.91 (2H, m), 6.96-6.92 (1H, m), 6.70 (1H, dd, J = 11.5, 8.4 Hz), 4.98 (1H, t, J = 11.5 Hz), 4.76 (1H, d, J = 6.2 Hz), 4.62 (2H, t, J = 6.2 Hz), 4.58-4.55 (1H, m), 4.05-3.77 (1H, m), 3.70-3.66 (2H, m), 3.52-3.25 (4H, m), 2.31-2.21 (2H, m), 2.18 (3H, s), 2.14 (3H, d, J = 9.2 Hz), 1.53 (3H, d, J = 6.6 Hz).; LC/MS RT 1.54 min, m/z [M − H]⁻ 578, 580

TABLE 18-32 Example Structural Formula Physical Property Value 156

1H-NMR (CDCl3) δ: 7.95-7.92 (2H, m), 6.94 (1H, dd, J = 8.3, 5.9 Hz), 6.68 (1H, dd, J = 11.4, 8.3 Hz), 4.95 (1H, d, J = 10.6 Hz), 4.51-4.45 (4H, m), 3.82-3.80 (1H, m), 3.58-3.51 (1H, m), 3.44 (1H, br s), 3.16-3.03 (2H, m), 2.18 (3H, s), 2.15 (3H, s), 2.02-1.98 (2H, m), 1.92-1.88 (2H, m), 1.53 (3H, d, J = 7.0 Hz); LC/MS RT 1.56 min, m/z [M − H]⁻ 592, 594 157

1H-NMR (CDCl3) δ: 10.23 (1H, s), 7.64 (1H, d, J = 8.4 Hz), 7.02 (1H, d, J = 8.4 Hz), 6.92 (1H, dd, J = 8.4, 5.9 Hz), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 6.30 (1H, d, J = 6.2 Hz), 5.58 (1H, d, J = 10.3 Hz), 5.23 (1H, s), 4.79 (1H, t, J = 10.4 Hz), 4.54-4.51 (1H, m), 4.21-4.17 (1H, m), 3.54 (1H, s), 3.48 (1H, s), 2.19 (3H, s), 2.18 (3H, s), 1.96 (3H, s), 1.53 (3H, d, J = 7.0 Hz); LC/MS RT 1.61 min, m/z [M − H]⁻ 551, 553 158

1H-NMR (CDCl3) δ: 8.12 (1H, br s), 7.37 (1H, d, J = 4.0 Hz), 6.97 (1H, dd, J = 8.3, 5.7 Hz), 6.68 (1H, d, J = 4.0 Hz), 6.72 (1H, dd, J = 11.7, 8.3 Hz), 5.24 (1H, br s), 4.84 (1H, t, J = 10.1 Hz), 3.48-3.43 (1H, m), 2.19 (3H, s), 2.17 (3H, s), 1.45 (3H, d, J = 7.0 Hz).; LC/MS RT 1.79 min, m/z [M − H]⁻ 444, 446 159

; LC/MS RT 1.65 min, m/z [M−H]⁻ 492 160

1H-NMR (CDCl3) δ: 8.52 (1H, br s), 7.48 (1H, s), 6.96-6.92 (1H, m), 6.73-6.68 (1H, m), 5.53 (1H, d, J = 9.5 Hz), 4.80 (1H, t, J = 9.5 Hz), 3.66 (3H, s), 3.48 (1H, br s), 2.21 (3H, s), 2.19 (3H, s), 1.56-1.55 (3H, m).; LC/MS RT 1.53 min, m/z [M − H]⁻ 442, 444

TABLE 18-33 Example Structural Formula Physical Property Value 161

1H-NMR (CDCl3) δ: 8.34-8.54 (1H, m), 7.98 (1H, dd, J = 8.5, 2.4 Hz), 7.65 (1H, d, J = 8.5 Hz), 6.93-6.89 (1H, m), 6.67 (1H, dd, J = 11.4, 8.4 Hz), 6.16-6.14 (1H, m), 4.91 (1H, t, J = 10.3 Hz), 3.51 (2H, br s), 2.16 (1H, s), 2.14 (3H, s), 2.12 (3H, s), 1.53 (3H, d, J = 7.0 Hz).; LC/MS RT 1.58 min, m/z [M − H]⁻ 506, 508 162

1H NMR (CDCl3) δ: 7.64 (dd, J = 8.1, 1.8 Hz, 1H), 7.60 (s, 1H), 6.97 (dd, J = 8.4, 5.5 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.71 (dd, J = 11.9, 8.1 Hz, 1H), 4.67 (d, J = 11.0 Hz, 1H), 3.53-3.56 (m, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 1.46 (d, J = 6.6 Hz, 3H); LC/MS RT 1.49 min, m/z [M − H]⁻ 459 163

1H NMR (CD3OD): δ: 8.11-8.21 (m, 2H), 7.90-7.98 (m, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.77 (d, J = 11.0 Hz, 1H), 3.53-3.72 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]⁻ 473 164

1H NMR (CD3OD) δ: 7.30 (dd, J = 8.1, 1.5 Hz, 1H), 7.01 (dd, J = 8.1, 1.5 Hz, 1H), 6.96 (dd, J = 8.4, 5.9 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 6.70 (dd, J = 11.9, 8.6 Hz, 1H), 4.74 (d, J = 11.0 Hz, 1H), 4.37-4.45 (m, 2H), 4.19-4.34 (m, 2H), 3.61-3.77 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 462 165

1H NMR (CD3OD) δ: 7.47 (dd, J = 8.4, 1.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.96 (dd, J = 8.3, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 3.53 (br dd, J = 10.8, 7.1 Hz, 1H), 2.17 (s, 3H), 2.15 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.42 min, m/z [M − H]⁻ 460

TABLE 18-34 Example Structural Formula Physical Property Value 166

LC/MS RT 1.59 min, m/z [M − H]⁻ 494 167

LC/MS RT 1.87, 1.92 min, m/z [M − H]⁻ 630, 632 168

1H NMR (CD3OD) δ: 7.40 (dd, J = 8.1, 1.5 Hz, 1H), 7.16 (dd, J = 8.1, 1.1 Hz, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.7 Hz, 1H), 6.72 (dd, J = 11.5, 8.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 4.63-4.66 (m, 2H), 3.50-3.59 (m, 1H), 2.17 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 475 169

1H NMR (CD3OD) δ: 8.30 (dd, J = 6.2, 2.2 Hz, 1H), 8.12 (ddd, J = 8.7, 4.5, 2.6 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.4 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 3.52-3.64 (m, 1H), 3.28 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 500 170

1H NMR (CD3OD) δ: 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.68-6.78 (m, 2H), 6.59-6.67 (m, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.94 (s, 3H), 3.63-3.75 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]⁻ 470

TABLE 18-35 Example Structural Formula Physical Property Value 171

1H NMR (CD3OD) δ: 8.22 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.1, 2.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.93-7.03 (m, 1H), 6.66-6.80 (m, 1H), 4.71 (d, J = 11.3 Hz, 1H), 3.51-3.64 (m, 1H), 3.07-3.26 (m, 4H), 2.64 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 1.55-1.71 (m, 6H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.89 min, m/z [M − H]⁻ 565 172

1H NMR (CD3OD) δ: 7.59 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.6, 1.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.70 (d, J = 11.0 Hz, 1H), 3.51-3.58 (m, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.39 min, m/z [M − H]⁻ 488 173

1H NMR (CD3OD) δ: 7.19-7.25 (m, 2H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 4.22-4.31 (m, 4H), 3.40-3.65 (m, 1H), 2.16 (s, 6H), 1.44 (d, J = 7.3 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 462 174

LC/MS RT 1.68 min, m/z [M − H]⁻ 472 175

1H NMR (CD3OD) δ: 8.05 (dd, J = 7.5, 2.0 Hz, 2H), 7.73 (t, J = 7.7 Hz, 1H), 6.97 (dd, J = 8.6, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.6 Hz, 1H), 5.52-5.71 (m, 2H), 4.72-4.79 (m, 1H), 3.54-3.61 (m, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 460

TABLE 18-36 Example Structural Formula Physical Property Value 176

1H NMR (CD3OD) δ: 8.43 (d, J = 2.2 Hz, 1H), 7.88-7.95 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.4, 8.4 Hz, 1H), 4.23 (d, J = 10.6 Hz, 1H), 3.43-3.55 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 517, 519 177

1H NMR (cdcl3) δ: 8.27 (brs, 1H), 7.77-7.89 (m, 2H), 7.40-7.59 (m, 3H), 6.94 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 5.31 (br d, J = 10.3 Hz, 1H), 4.82 (t, J = 10.3 Hz, 1H), 3.36-3.47 (m, 1H), 2.17 (s, 3H), 2.15 (s, 3H), 1.43 (d, J = 5.9 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 404 178

LC/MS RT 1.75 min, m/z [M − H]⁻ 498 179

LC/MS RT 1.64 min, m/z [M − H]⁻ 474 180

LC/MS RT 1.90 min, m/z [M − H]⁻ 541, 543

TABLE 18-37 Example Structural Formula Physical Property Value 181

1H NMR (CD3OD) δ: 8.38 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.83 (dd, J = 8.8, 1.8 Hz, 1H), 6.95 (dd, J = 8.3, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.3 Hz, 1H), 4.75 (d, J = 11.0 Hz, 1H), 3.50-3.65 (m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.50 min, m/z [M − H]⁻ 445 182

1H NMR (CD3OD) δ: 8.28 (s, 1H), 8.19 (s, 1H), 7.73 (dd, J = 8.8, 1.5 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.94 (dd, J = 8.4, 5.9 Hz, 1H), 6.69 (dd, J = 11.7, 8.4 Hz, 1H), 4.72 (d, J = 11.4 Hz, 1H), 3.47-3.65 (m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H); LC/MS RT 1.53 min, m/z [M − H]⁻ 444 183

1H NMR (CD3OD) δ: 7.40-7.48 (m, 2H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.69-6.79 (m, 2H), 4.65 (d, J = 11.4 Hz, 1H), 4.16-4.22 (m, 2H), 3.48-3.60 (m, 1H), 2.78 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H), 1.94-2.04 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 460 184

1H NMR (CD3OD) δ: 6.84-7.00 (m, 4H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 3.47-3.56 (m, 1H), 3.20-3.28 (m, 2H), 2.89 (s, 3H), 2.72 (t, J = 6.4 Hz, 2H), 2.15-2.18 (m, 6H), 1.85-1.99 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.73 min, m/z [M − H]⁻ 473 185

1H-NMR (CDCl3) δ: 8.47 (1H, br s), 7.70 (1H, d, J = 8.8 Hz), 7.02 (1H, dd, J = 8.2, 6.0 Hz), 6.97 (1H, dd, J = 8.4, 1.8 Hz), 6.90-6.89 (1H, m), 6.72 (1H, t, J = 8.8 Hz), 5.74-5.73 (1H, m), 5.67 (1H, br s), 5.30-5.30 (1H, m), 5.14 (1H, d, J = 9.2 Hz), 3.92 (3H, s), 2.19 (3H, s), 2.11 (3H, s).; LC/MS RT 1.80 min, m/z [M − H]⁻ 466, 468

TABLE 18-38 Example Structural Formula Physical Property Value 186

1H NMR (CD3OD) δ: 7.69-7.82 (m, 1H), 6.91-7.10 (m, 2H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.74 (d, J = 11.0 Hz, 1H), 3.59-3.71 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.66 (s, 6H), 1.46 (d, J = 6.6 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]⁻ 498 187

1H NMR (CD3OD) δ: 7.94 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.98-7.07 (m, 2H), 6.90-6.98 (m, 1H), 4.43 (d, J = 10.3 Hz, 1H), 3.19-3.27 (m, 1H), 2.74-2.91 (m, 4H), 1.90-2.08 (m, 2H), 1.71 (s, 3H), 1.65 (s, 3H), 1.42 (d, J = 7.0 Hz, 3H); LC/MS RT 1.93 min, m/z [M − H]⁻ 490, 492 188

1H NMR (CD3OD) δ: 8.29 (d, J = 2.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.45 (dd, J = 8.2, 2.4 Hz, 1H), 6.90-7.10 (m, 3H), 4.34 (d, J = 10.6 Hz, 1H), 3.24- 3.31 (m, 1H), 2.79-2.84 (m, 4H), 1.90-2.09 (m, 2H), 1.70 (s, 6H), 1.39 (d, J = 7.0 Hz, 3H); LC/MS RT 1.8 min, m/z [M − H]⁻ 534, 536 189

1H NMR (CD3OD) δ: 7.69-7.76 (m, 1H), 6.89-7.14 (m, 4H), 4.39 (d, J = 11.0 Hz, 1H), 3.24-3.31 (m, 1H), 2.77-2.97 (m, 4H), 1.91-2.07 (m, 2H), 1.67 (s, 6H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]⁻ 492 190

1H NMR (CD3OD) δ: 7.37-7.50 (m, 1H), 7.03 (s, 2H), 6.91-6.99 (m, 1H), 4.41 (d, J = 10.6 Hz, 1H), 4.06 (s, 3H), 3.32-3.36 (m, 1H), 2.77-2.96 (m, 4H), 1.93-2.06 (m, 2H), 1.54 (s, 3H), 1.50 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 492

TABLE 18-39 Example Structural Formula Physical Property Value 191

1H NMR (CD3OD) δ: 7.76 (d, J = 9.2 Hz, 1H), 6.97-7.08 (m, 2H), 6.81-6.95 (m, 2H), 4.32 (d, J = 11.0 Hz, 1H), 3.91 (s, 6H), 3.33-3.40 (m, 1H), 2.70- 2.98 (m, 4H), 1.91-2.13 (m, 2H), 1.66 (s, 3H), 1.65 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]⁻ 516 192

1H NMR (CD3OD) δ: 8.45-8.43 (2H, m), 8.02 (1H, d, J = 8.1 Hz), 7.82 (1H, d, J = 8.1 Hz), 7.04-7.02 (2H, m), 6.98-6.95 (1H, m), 4.63 (1H, s), 4.51 (1H, d, J = 11.0 Hz), 2.92-2.82 (4H, m), 2.05-1.97 (2H, m), 1.69 (3H, s), 1.68 (3H, s), 1.42 (3H, d, J = 7.0 Hz); LC/MS RT 1.74 min, m/z [M − H]⁻ 491, 493 193

1H NMR (CD3OD) δ: 8.04 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.83 (d, J = 11.4 Hz, 1H), 3.55-3.68 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.67 (d, J = 6.6 Hz, 6H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]⁻ 497, 499 194

1H NMR (CD3OD) δ: 8.01-8.15 (m, 1H), 7.46-7.69 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.93-7.01 (m, 1H), 6.66-6.76 (m, 1H), 4.69 (d, J = 11.4 Hz, 1H), 3.47-3.61 (m, 1H), 2.72-2.88 (m, 2H), 2.07-2.25 (m, 6H), 1.76-1.94 (m, 4H), 1.39-1.52 (m, 6H); LC/MS RT 1.66 min, m/z [M − H]⁻ 488 195

1H NMR (CD3OD) δ: 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.50 (dt, J = 8.7, 2.6 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.77-6.83 (m, 1H), 6.68-6.76 (m, 1H), 4.67 (dd, J = 11.2, 3.1 Hz, 1H), 4.29-4.38 (m, 1H), 4.21-4.28 (m, 1H), 3.47- 3.62 (m, 1H), 2.13-2.24 (m, 6H), 2.02-2.11 (m, 2H), 1.58 (d, J = 11.0 Hz, 3H), 1.39-1.49 (m, 3H); LC/MS RT 1.60 min, m/z [M − H]⁻ 490

TABLE 18-40 Example Structural Formula Physical Property Value 196

1H NMR (CD3OD) δ: 8.25 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 11.0 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.51-3.62 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.57 (s, 6H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min m/z [M − H]⁻ 523 197

1H NMR (CD3OD) δ: 8.02 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 8.1, 1.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.49-3.62 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.53 (s, 6H), 1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.52 min, m/z [M − H]⁻ 505 198

1H NMR (CD3OD) δ: 8.41 (s, 1H), 7.60 (s, 1H), 6.97 (dd, J = 8.3, 6.0 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.52-3.64 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.68 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 539, 541 199

1H NMR (CD3OD) δ: 8.25 (d, J = 1.8 Hz, 1H), 7.95 (dd, J = 7.9, 2.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 6.93-7.02 (m, 1H), 6.66-6.75 (m, 1H), 4.75-4.85 (m, 1H), 3.52-3.62 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.88 (s, 6H), 1.40 (d, J = 6.2 Hz, 3H); LC/MS RT 1.63 min, m/z [M − H]⁻ 553 200A

1H NMR (CD3OD) δ: 7.61 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.96 (dd, J = 8.2, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H), 4.40-4.46 (m, 1H), 4.26 (td, J = 10.8, 2.6 Hz, 1H), 3.62-3.71 (m, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 2.05-2.13 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]⁻ 527, 529

TABLE 18-41 Example Structural Formula Physical Property Value 200B

1H NMR (CD3OD) δ: 7.59 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.41-4.48 (m, 1H), 4.32 (td, J = 10.7, 2.7 Hz, 1H), 3.63-3.73 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 2.05-2.13 (m, 2H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]⁻ 527, 529 201

1H NMR (CD3OD) δ: 7.90 (dd, J = 8.6, 2.7 Hz, 1H), 7.47 (dd, J = 8.4, 2.2 Hz, 1H), 6.98-7.05 (m, 2H), 6.91-6.95 (m, 1H), 5.67 (dd, J = 6.8, 5.3 Hz, 1H), 4.34 (d ,J = 11.0 Hz, 1H), 3.39-3.48 (m, 1H), 2.75-2.95 (m, 4H), 1.92-2.05 (m, 2H), 1.57 (d, J = 7.0 Hz, 3H), 1.44 (dd, J = 6.6, 1.5 Hz, 3H); LC/MS RT 1.74 min, m/z [M − H]⁻ 510, 512 202

1H NMR (CD3OD) δ: 7.98 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.00- 7.04 (m, 2H), 6.93-6.98 (m 1H), 5.19-5.29 (m, 1H), 4.48-4.54 (m, 1H), 3.33-3.42 (m, 1H), 2.70-3.01 (m, 4H), 1.97-2.10 (m, 2H), 1.38-1.52 (m, 6H); LC/MS RT 1.66 min, m/z [M − H]⁻ 477, 479 203

1H NMR (CD3OD) δ: 7.64-7.72 (m, 1H), 7.27 (dd, J = 8.4, 1.5 Hz, 1H), 6.95-7.02 (m, 2H), 6.90-6.94 (m, 1H), 5.34-5.48 (m, 1H), 4.38 (d, J = 11.0 Hz, 1H), 4.00 (s, 3H), 3.60-3.76 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 1.57- 1.65 (m, 3H), 1.37 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68, 1.74 min, m/z [M − H]⁻ 494, 496 204

1H NMR (CD3OD) δ: 7.69 (dd, J = 8.4, 7.0 Hz, 1H), 7.28 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (dd, J = 8.5, 5.7 Hz, 1H), 6.69 (dd, J = 11.7, 8.5 Hz, 1H), 5.30-5.52 (m, 1H), 4.70-4.77 (m, 1H), 4.01 (d, J = 1.5 Hz, 3H), 3.61-3.74 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.57-1.64 (m, 3H), 1.41-1.48 (m, 3H); LC/MS RT 1.70, 1.75 min, m/z [M − H]⁻ 512, 514

TABLE 18-42 Example Structural Formula Physical Property Value 205

1H NMR (CD3OD) δ: 8.09-8.21 (m, 1H), 7.74-7.92 (m, 2H), 7.68-7.73 (m, 1H), 7.39-7.64 (m, 2H), 7.24-7.30 (m, 1H), 7.15-7.23 (m, 1H), 5.30-5.55 (m, 1H), 4.16-4.35 (m, 1H), 4.03 (d, J = 2.6 Hz, 3H), 3.80 (d, J = 9.5 Hz, 1H), 1.55-1.67 (m, 3H), 1.27-1.41 (m, 3H); LC/MS RT 1.72 1.77 min, m/z [M − H]⁻ 534, 536 206A

1H NMR (CD3OD) δ: 7.69 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 8.4, 5.7 Hz, 1H), 6.73 (dd, J = 11.7, 8.3 Hz, 1H), 5.40-5.48 (m, 1H), 4.72 (d, J = 11.5 Hz, 1H), 4.01 (s, 3H), 3.64-3.75 (m, 1H), 2.51-2.60 (m, 2H), 2.25 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.46 (d, J = 6.1 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]⁻ 526, 528 207A

1H-NMR (CDCl3) δ: 7.78 (1H, br s), 7.67 (1H, d, J = 8.4 Hz), 6.99 (1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 8.3, 5.9 Hz), 6.70 (1H, dd, J = 11.5, 8.3 Hz), 5.41 (1H, d, J = 10.4 Hz), 4.89 (1H, t, J = 10.4 Hz), 4.49-4.44 (1H, m), 4.32-4.25 (1H, m), 3.46 (1H, br s), 3.25 (1H, s), 2.36-2.29 (1H, m), 2.19 (3H, s), 2.18 (3H, s), 2.10-2.05 (1H, m), 1.79 (3H, s), 1.55-1.53 (3H, m); LC/MS RT 1.64 min, m/z [M − H]⁻ 524, 526 207B

1H-NMR (CDCl3) δ: 8.41 (1H, s), 7.64 (1H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 8.2, 5.9 Hz), 6.70 (1H, dd, J = 11.5, 8.2 Hz), 5.40 (1H, d, J = 11.0 Hz), 4.85 (1H, t, J = 11.0 Hz), 4.45-4.44 (1H, m), 4.33- 4.30 (1H, m), 3.48 (1H, s), 3.40 (1H, s), 2.32-2.30 (1H, m), 2.19-2.16 (6H, M), 2.14-2.12 (1H, m), 1.78 (3H, s), 1.57-1.55 (3H, m); LC/MS RT 1.71 min, m/z [M − H]⁻ 524, 526 208A

1H NMR (cd3od) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.3, 6.0 Hz, 1H), 6.69 (dd, J = 11.7, 8.3 Hz, 1H), 5.49 (q, J = 6.6 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.00 (s, 3H), 3.60-3.74 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]⁻ 512, 514

TABLE 18-43 Example Structural Formula Physical Property Value 208B

1H NMR (CD3OD) δ: 7.70 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.3, 6.0 Hz, 1H), 6.69 (dd, J = 11.7, 8.3 Hz, 1H), 5.38 (q, J = 6.6 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.00 (s, 3H), 3.60-3.74 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]⁻ 512, 514 209A

1H-NMR (CDCl3) δ: 8.15 (1H, s), 7.66 (1H, d, J = 8.4 Hz), 7.19 (1H, dd, J = 8.6, 5.1 Hz), 6.99 (1H, d, J = 8.6 Hz), 6.78 (1H, dd, J = 10.8, 9.0 Hz), 5.52 (1H, d, J = 11.0 Hz), 4.87 (1H, t, J = 10.4 Hz), 4.47-4.44 (1H, m), 4.28- 4.25 (1H, m), 3.48 (1H, s), 3.29 (1H, s), 2.37 (3H, s), 2.32-2.28 (1H, m), 2.09-2.06 (1H, m), 1.78 (3H, s), 1.54 (3H, d, J = 7.0 Hz).; LC/MS RT 1.68 min, m/z [M − H]⁻ 544, 546 209B

1H-NMR (CDCl3) δ: 8.68 (1H, br s), 7.64 (1H, d, J = 8.8 Hz), 7.19 (1H, dd, J = 8.8, 4.9 Hz), 7.01 (1H, d, J = 8.8 Hz), 6.78 (1H, dd, J = 10.8, 8.8 Hz), 5.47-5.42 (1H, m), 4.81 (1H, t, J = 10.9 Hz), 4.45-4.42 (1H, m), 4.32 (1H, t, J = 10.9 Hz), 3.53 (1H, br s), 3.40 (1H, br s), 2.35 (3H, s), 2.33-2.27 (1H, m), 2.15-2.10 (1H, m), 1.78 (3H, s), 1.59-1.58 (3H, m).; LC/MS RT 1.74 min, m/z [M − H]⁻ 544, 546 210

LC/MS RT 1.66 min, m/z [M − H]⁻ 482, 484 211A

1H-NMR (CDCl3) δ: 8.04 (1H, s), 7.86 (1H, dd, J = 8.2, 1.5 Hz), 7.77 (1H, d, J = 8.2 Hz), 7.03 (1H, t, J = 8.2 Hz), 6.92 (1H, dd, J = 8.3, 5.9 Hz), 6.68 (1H, dd, J = 11.5, 8.3 Hz), 5.58 (1H, d, J = 10.2 Hz), 4.86 (1H, t, J = 10.2 Hz), 4.48-4.43 (2H, m), 3.60 (1H, s), 3.25 (1H, s), 2.40-2.33 (1H, m), 2.24-2.20 (1H, m), 2.20 (3H, s), 2.18 (3H, s), 1.53 (3H, d, J = 7.0 Hz).; LC/MS RT 1.67 min, m/z [M − H]⁻ 544

TABLE 18-44 Example Structural Formula Physical Property Value 212

1H NMR (CD3OD) δ: 7.68 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.94- 7.06 (m, 1H), 6.67-6.76 (m, 1H), 4.73-4.80 (m, 1H), 3.92 (s, 3H), 3.67- 3.77 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 1.83 (s, 3H), 1.78 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.84 min, m/z [M − H]⁻ 526, 528 213

LC/MS RT 1.47 min, m/z [M − H]⁻ 483, 485 214

LC/MS RT 1.49 min, m/z [M − H]⁻ 527, 529 215

LC/MS RT 1.49 min, m/z [M − H]⁻ 483, 485 216

1H NMR (CD3OD) δ: 8.19 (d, J = 5.9 Hz, 1H), 6.98 (dd, J = 8.1, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 5.35-5.44 (m, 1H), 4.86-4.91 (m, 1H), 4.03- 4.06 (m, 3H), 3.66-3.77 (m, 1H), 2.27 (s, 3H), 2.20 (s, 3H), 1.56-1.63 (m, 3H), 1.51 (d, J = 6.6 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]⁻ 513, 515

TABLE 18-45 Example Structural Formula Physical Property Value 217

LC/MS RT 1.73 min, m/z [M − H]⁻ 500, 502 218

LC/MS RT 1.74 min, m/z [M − H]⁻ 496, 498 219

LC/MS RT 1.59 min, m/z [M − H]⁻ 500, 502 220A

1H-NMR (CDCl3) δ: 8.07 (1H, s), 7.86 (1H, d, J = 8.8 Hz), 7.07 (1H, d, J = 8.8 Hz), 6.94 (1H, dd, J = 8.3, 5.7 Hz), 6.70 (1H, dd, J = 11.7, 8.3 Hz), 5.49 (1H, d, J = 9.9 Hz), 4.86 (1H, t, J = 10.1 Hz), 4.74 (1H, s), 4.61-4.51 (1H, m), 4.39 (1H, t, J = 12.5 Hz), 3.49 (1H, s), 2.57-2.53 (1H, m), 2.36-2.34 (1H, m), 2.20-2.17 (6H, m), 1.52 (3H, d, J = 7.0 Hz).; LC/MS RT 1.74 min, m/z [M − H]⁻ 578, 580 220B

1H-NMR (CDCl3) δ: 8.26 (1H, s), 7.79 (1H, d, J = 8.6 Hz), 7.06 (1H, d, J = 8.6 Hz), 6.96-6.93 (1H, m), 6.73-6.68 (1H, m), 5.40 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 4.53-4.46 (3H, m), 3.41 (1H, s), 2.61-2.57 (1H, m), 2.37-2.34 (1H, m), 2.19-2.16 (6H, m), 1.52 (3H, d, J = 7.0 Hz).; LC/MS RT 1.80 min, m/z [M − H]⁻ 578, 580

TABLE 18-46 Example Structural Formula Physical Property Value 221

1H-NMR (CDCl3) δ: 8.51-8.51 (1H, m), 8.28-8.27 (1H, m), 6.93 (1H, dd, J = 8.4, 5.9 Hz), 6.71-6.64 (1H, m), 6.05 (1H, br s), 5.60-5.55 (1H, m), 5.03- 4.98 (1H, m), 3.54 (1H, s), 2.17 (6H, d, J = 3.7 Hz), 1.49 (3H, d, J = 7.0 Hz); LC/MS RT 1.72 min, m/z [M − H]⁻ 537, 539 222A

1H NMR (CD3OD) δ: 7.61 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 9.0, 5.3 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 11.2, 9.0 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.39-4.47 (m, 1H), 4.22-4.33 (m, 1H), 3.63-3.78 (m, 1H), 2.44 (s, 3H), 2.17-2.24 (m, 1H), 2.05-2.15 (m, 1H), 1.75 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]⁻ 588, 590 222B

1H NMR (CD3OD) δ: 7.60 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 8.9, 5.1 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 11.2, 8.9 Hz, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.39-4.47 (m, 1H), 4.33 (td, J = 10.8, 2.6 Hz, 1H), 3.65-3.77 (m, 1H), 2.44 (s, 3H), 2.22-2.31 (m, 1H), 2.05-2.12 (m, 1H), 1.75 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]⁻ 588, 590 223

LC/MS RT 1.61 min, m/z [M − H]⁻ 506 224A

1H NMR (CD3OD) δ: 7.70 (dd, J = 8.6, 5.9 Hz, 1H), 6.96 (dd, J = 8.6, 5.9 Hz, 1H), 6.61-6.82 (m, 2H), 4.70 (d, J = 11.4 Hz, 1H), 4.29-4.49 (m, 2H), 3.60- 3.79 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 2.04-2.12 (m, 2H), 1.67 (d, J = 1.8 Hz, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.6 min, m/z [M − H]⁻ 508

TABLE 18-47 Example Structural Formula Physical Property Value 224B

1H NMR (CD3OD) δ: 7.70 (dd, J = 8.8, 5.9 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.68-6.75 (m, 2H), 4.74 (d, J = 11.4 Hz, 1H), 4.38 (t, J = 5.5 Hz, 2H), 3.63-3.71 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 2.03-2.12 (m, 2H), 1.66 (d, J = 1.8 Hz, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 508 225A

1H NMR (CD3OD) δ: 7.79 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.64-4.69 (m, 1H), 4.42-4.49 (m, 1H), 3.61-3.76 (m, 1H), 2.25-2.41 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 2.01-2.11 (m, 1H), 1.62 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 558 226A

1H NMR (CD3OD) δ: 7.61 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.6, 5.1 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.81 (dd, J = 11.4, 8.6 Hz, 1H), 4.69 (d, J = 11.0 Hz, 1H), 4.35-4.46 (m, 1H), 4.26 (td, J = 10.9, 2.7 Hz, 1H), 3.66-3.75 (m, 1H), 2.44 (s, 3H), 2.15-2.26 (m, 1H), 2.05-2.13 (m, 1H), 1.52 (d, J = 6.6 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]⁻ 591, 593 226B

LC/MS RT 1.76 min, m/z [M − H]⁻ 591, 593 227A

1H NMR (CD3OD) δ: 7.70 (dd, J = 8.8, 5.9 Hz, 1H), 7.42 (dd, J = 8.8, 5.1 Hz, 1H), 6.80 (dd, J = 11.0, 9.0 Hz, 1H), 6.72 (dd, J = 11.0, 9.0 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 4.31-4.42 (m, 2H), 3.66-3.74 (m, 1H), 2.42 (s, 3H), 2.04- 2.15 (m, 2H), 1.67 (d, J = 1.8 Hz, 3H), 1.52 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]⁻ 572, 574

TABLE 18-48 Example Structural Formula Physical Property Value 227B

1H NMR (CD3OD) δ: 7.71 (dd, J = 8.8, 5.9 Hz, 1H), 7.43 (dd, J = 9.0, 5.3 Hz, 1H), 6.82 (dd, J = 11.4, 8.8 Hz, 1H), 6.73 (dd, J = 10.6, 8.8 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.38 (t, J = 5.5 Hz, 2H), 3.65-3.72 (m, 1H), 2.44 (s, 3H), 2.05-2.13 (m, 2H), 1.66 (d, J = 1.8 Hz, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]⁻ 572, 574 228A

1H NMR (CD3OD) δ: 7.61 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.8, 5.1 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 11.0, 8.8 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.41-4.47 (m, 1H), 4.26 (td, J = 10.9, 2.4 Hz, 1H), 3.65-3.72 (m, 1H), 2.39 (s, 3H), 2.15-2.25 (m, 1H), 2.05-2.13 (m, 1H), 1.52 (d, J = 6.6 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]⁻ 547, 549 228B

1H NMR (CD3OD) δ: 7.60 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 9.0, 4.9 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 11.2, 9.0 Hz, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.41-4.46 (m, 1H), 4.29-4.36 (m, 1H), 3.64-3.74 (m, 1H), 2.38 (s, 3H), 2.22-2.29 (m, 1H), 2.05-2.13 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.74 min, m/z [M − H]⁻ 547, 549 229A

1H NMR (CD3OD) δ: 7.70 (dd, J = 8.8, 5.9 Hz, 1H), 7.42 (dd, J = 8.8, 5.1 Hz, 1H), 6.80 (dd, J = 11.2, 9.0 Hz, 1H), 6.72 (dd, J = 10.8, 9.0 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 4.31-4.42 (m, 2H), 3.66-3.74 (m, 1H), 2.44 (s, 3H), 2.05- 2.11 (m, 2H), 1.67 (d, J = 1.8 Hz, 3H), 1.52 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]⁻ 528, 530 229B

1H NMR (CD3OD) δ: 7.71 (dd, J = 8.9, 5.9 Hz, 1H), 7.43 (dd, J = 8.9, 5.3 Hz, 1H), 6.82 (dd, J = 11.4, 8.8 Hz, 1H), 6.73 (dd, J = 10.6, 8.8 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.38 (t, J = 5.5 Hz, 2H), 3.63-3.78 (m, 1H), 2.44 (s, 3H), 2.04-2.16 (m, 2H), 1.66 (d, J = 1.8 Hz, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]⁻ 528, 530

TABLE 18-49 Example Structural Formula Physical Property Value 230A

1H NMR (CD3OD) δ: 7.73 (dd, J = 8.8, 6.2 Hz, 1H), 6.96 (dd, J = 8.4, 5.9 Hz, 1H), 6.66-6.77 (m, 2H), 4.69 (d, J = 11.4 Hz, 1H), 4.84-4.90 (m, 1H), 4.53- 4.60 (m, 1H), 4.35 (ddd, J = 13.1, 10.9, 2.4 Hz, 1H), 3.62-3.71 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.95-2.12 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]⁻ 494 230B

1H NMR (CD3OD) δ: 7.77 (dd, J = 8.8, 6.2 Hz, 1H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.68-6.78 (m, 2H), 4.85-4.93 (m, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.51- 4.60 (m, 1H), 4.33 (td, J = 11.5, 3.3 Hz, 1H), 3.62-3.71 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.96-2.09 (m, 2H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 494 231

1H NMR (CD3OD) δ: 8.04-8.10 (m, 1H), 7.54-7.61 (m, 1H), 7.38-7.46 (m, 1H), 6.94-7.09 (m, 3H), 5.17 (q, J = 6.5 Hz, 1H), 4.36 (dd, J = 10.6, 5.1 Hz, 1H), 3.24-3.33 (m, 1H), 2.77-2.91 (m, 4H), 1.90-2.07 (m, 2H), 1.38-1.42 (m, 6H); LC/MS RT 1.72 min, m/z [M − H]⁻ 476, 478 232

1H NMR (CD3OD) δ: 7.59-7.69 (m, 3H), 7.46 (dd, J = 7.3, 1.1 Hz, 1H), 7.30-7.38 (m, 1H), 7.22-7.29 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 4.85-4.90 (m, 1H), 4.63-4.72 (m, 1H), 4.50-4.59 (m, 1H), 4.39 (d, J = 10.6 Hz, 1H), 4.26-4.35 (m, 1H), 2.96 (s, 3H), 1.97-2.05 (m, 2H), 1.68 (d, J = 6.6 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 528, 530 233

1H NMR (CD3OD) δ: 8.10 (d, J = 8.4 Hz, 1H), 7.75-7.93 (m, 2H), 7.63-7.75 (m, 1H), 7.51-7.60 (m, 1H), 7.39-7.48 (m, 1H), 7.16-7.29 (m, 1H), 7.05 (t, J = 9.0 Hz, 1H), 4.91-4.93 (m, 1H), 4.56-4.64 (m, 2H), 4.28-4.45 (m, 1H), 4.17-4.27 (m, 1H), 1.98-2.13 (m, 2H), 1.64 (d, J = 6.6 Hz, 3H); LC/MS RT 1.63, 1.68 min, m/z [M − H]⁻ 532, 534

TABLE 18-50 Example Structural Formula Physical Property Value 234A

1H-NMR (CDCl3) δ: 7.99 (1H, d, J = 8.8 Hz), 7.78 (1H, d, J = 8.1 Hz), 7.72-7.68 (2H, m), 7.65 (1H, s), 7.56 (1H, t, J = 7.9 Hz), 7.43 (1H, t, J = 7.3 Hz), 7.18-7.12 (1H, m), 6.99 (1H, d, J = 8.4 Hz), 5.57 (1H, d, J = 10.6 Hz), 5.05-5.00 (1H, m), 4.93 (1H, s), 4.51-4.48 (1H, m), 4.40- 4.33 (1H, m), 4.00 (1H, s), 2.47 (1H, s), 2.16-2.07 (2H, m), 1.69-1.68 (3H, m).; LC/MS RT 1.63 min, m/z [M − H]⁻ 532, 534 235A

1H NMR (CD3OD) δ: 7.66 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.1, 5.5 Hz, 1H), 6.69 (dd, J = 11.7, 8.4 Hz, 1H), 4.86-4.93 (m, 1H), 4.71 (d, J = 11.4 Hz, 1H), 4.53-4.61 (m, 1H), 4.29-4.39 (m, 1H), 3.63-3.71 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 2.01-2.06 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 510, 512 235B

1H NMR (CD3OD) δ: 7.70 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.92-4.95 (m, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.53-4.60 (m, 1H), 4.26-4.39 (m, 1H), 3.58-3.75 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.95-2.14 (m, 2H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 510, 512 236

1H NMR (CD3OD) δ: 7.71-7.88 (m, 2H), 7.31-7.42 (m, 1H), 6.93-7.04 (m, 1H), 6.65-6.77 (m, 1H), 5.53-5.80 (m, 1H), 4.72-4.89 (m, 1H), 3.54- 3.66 (m, 1H), 2.20 (d, J = 2.2 Hz, 3H), 2.17 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H), 1.42-1.47 (m, 3H); LC/MS RT 1.70, 1.75 min, m/z [M − H]⁻ 482, 484 237A

1H-NMR (CDCl3) δ: 7.72-7.69 (1H, m), 7.61-7.59 (1H, m), 7.45 (1H, s), 6.99-6.90 (2H, m), 6.70-6.65 (1H, m), 5.34-5.32 (1H, m), 4.89-4.81 (2H, m), 3.49 (1H, br s), 2.35 (1H, s), 2.25 (1H, dd, J = 14.4, 6.0 Hz), 2.19 (3H, s), 2.17 (3H, s), 1.97 (1H, dd, J = 14.4, 7.3 Hz), 1.55-1.54 (6H, m), 1.48 (3H, s).; LC/MS RT 1.66 min, m/z [M − H]⁻ 504, 506

TABLE 18-51 Example Structural Formula Physical Property Value 238A

1H NMR (CD3OD) δ: 7.67 (d, J = 8.5 Hz, 1H), 7.08-7.17 (m, 1H), 7.04-7.07 (m, 1H), 6.86 (dd, J = 11.1, 8.9 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.89-4.94 (m, 1H), 4.53-4.61 (m, 1H), 4.29-4.40 (m, 1H), 3.64-3.77 (m, 1H), 2.38 (s, 3H), 2.00-2.12 (m, 2H), 1.51 (d, J = 7.6 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]⁻ 530, 532 239A

1H NMR (CD3OD) δ: 7.67 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.4 Hz, 1H), 4.89-4.94 (m, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.51-4.61 (m, 1H), 4.27-4.43 (m, 1H), 3.59-3.77 (m, 1H), 2.47-2.68 (m, 2H), 2.25 (s, 3H), 2.03-2.13 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]⁻ 524, 526 240

1H NMR (CD3OD) δ: 7.76 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 8.3, 6.0 Hz, 1H), 6.70 (dd, J = 11.7, 8.3 Hz, 1H), 5.60 (t, J = 3.1 Hz, 1H), 4.67 (d, J = 11.0 Hz, 1H), 3.44-3.51 (m, 1H), 2.96-3.06 (m, 1H), 2.52- 2.65 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.97-2.10 (m, 2H), 1.78-1.84 (m, 1H), 1.66-1.77 (m, 1H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.89 min, m/z [M − H]⁻ 508, 510 241

1H NMR (CD3OD) δ: 7.69-7.88 (m, 1H), 6.93-7.11 (m, 1H), 6.66-6.84 (m, 2H), 4.88-4.93 (m, 1H), 4.64-4.80 (m, 1H), 4.48-4.64 (m, 1H), 4.22-4.43 (m, 1H), 3.62-3.69 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 1.93-2.09 (2H, m), 1.44-1.52 (m, 3H); LC/MS RT 1.57, 1.61 min, m/z [M − H]⁻ 494 242

1H NMR (CD3OD) δ: 6.94-7.02 (m, 1H), 6.67-6.78 (m, 1H), 6.53-6.65 (m, 1H), 4.79-4.87 (m, 1H), 4.48-4.71 (m, 2H), 4.25-4.42 (m, 1H), 3.57-3.82 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.95-2.11 (m, 2H), 1.50 (d, J = 6.2 Hz, 3H); LC/MS RT 1.59, 1.62 min, m/z [M − H]⁻ 512

TABLE 18-52 Example Structural Formula Physical Property Value 243A

1H NMR (CD3OD) δ: 7.67 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 8.8, 5.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 11.0, 8.8 Hz, 1H), 4.90-4.95 (m, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.54-4.59 (m, 1H), 4.30-4.37 (m, 1H), 3.63-3.78 (m, 1H), 2.43 (s, 3H), 2.03-2.19 (m, 2H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 574, 576 234B

1H NMR (CD3OD) δ: 7.70 (d, J = 8.7 Hz, 1H), 7.43 (dd, J = 8.8, 5.1 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.82 (dd, J = 11.2, 8.8 Hz, 1H), 4.92-4.95 (m, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.53-4.58 (m, 1H), 4.28-4.37 (m, 1H), 3.65-3.75 (m, 1H), 2.44 (s, 3H), 1.95-2.13 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 574, 576 244A

1H NMR (CD3OD) δ: 7.85 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.96 (dd, J = 8.4, 5.9 Hz, 1H), 6.69 (dd, J = 11.7, 8.4 Hz, 1H), 5.00-5.04 (m, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.59-4.68 (m, 1H), 4.49-4.56 (m, 1H), 3.64-3.72 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 2.00-2.13 (m, 2H), 1.51 (d, J = 6.6 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]⁻ 544 244B

1H NMR (CD3OD) δ: 7.89 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 5.04-5.07 (m, 1H), 4.79 (d, J = 11.0 Hz, 1H), 4.46-4.65 (m, 2H), 3.63-3.77 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.95-2.14 (m, 2H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]⁻ 544 245

1H NMR (CD3OD) δ: 8.51 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 6.98 (dd, J = 8.3, 6.0 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.89-4.94 (m, 1H), 3.63-3.70 (m, 1H), 2.26 (s, 3H), 2.20 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); LC/MS RT 1.47 min, m/z [M − H]⁻ 482, 484

TABLE 18-53 Example Structural Formula Physical Property Value 246

1H NMR (CD3OD) δ: 7.73-7.97 (m, 1H), 7.51-7.68 (m, 1H), 7.46 (s, 1H), 6.99 (dd, J = 8.4, 5.7 Hz, 1H), 6.73 (dd, J = 11.8, 8.4 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 3.54-3.66 (m, 1H), 3.11 (s, 3H), 2.88 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H), 1.44-1.54 (m, 3H); LC/MS RT 1.79 min, m/z [M − H]⁻ 509, 511 247

1H NMR (CD3OD) δ: 7.84 (d, J = 8.1 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 6.96-7.01 (m, 1H), 6.71-6.75 (m, 1H), 4.74-4.85 (m, 1H), 3.93-4.32 (m, 4H), 3.53-3.67 (m, 1H), 2.32-2.46 (m, 2H), 2.21 (s, 3H), 2.18 (s, 3H), 1.43 (d, J = 7.3 Hz, 3H); LC/MS RT 1.81 min, m/z [M − H]⁻ 521, 523 248

1H NMR (CD3OD) δ: 7.52-7.89 (m, 3H), 6.94-7.03 (m, 1H), 6.66-6.78 (m, 1H), 4.79 (d, J = 11.4 Hz, 1H), 3.43-3.88 (m, 5H), 2.21 (s, 3H), 2.15 (s, 3H), 1.49 (d, J = 7.7 Hz, 3H),; LC/MS RT 1.61, 1.66 min, m/z [M − H]⁻ 525, 527 249

1H NMR (CD3OD) δ: 8.51 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.9, 5.1 Hz, 1H), 6.88 (dd, J = 11.2, 8.9 Hz, 1H), 4.92 (d, J = 11.4 Hz, 1H), 3.61-3.74 (m, 1H), 2.42 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.51 min, m/z [M − H]⁻ 502, 504 250

1H NMR (CD3OD) δ: 8.61 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.92 (d, J = 11.0 Hz, 1H), 3.56-3.83 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H); LC/MS RT 1.49 min, m/z [M − H]⁻ 526, 528

TABLE 18-54 Example Structural Formula Physical Property Value 251

1H NMR (CD3OD) δ: 8.60 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.2, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.88-4.93 (m, 1H), 3.55-3.75 (m, 1H), 2.93 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]⁻ 542, 544 252

1H NMR (CD3OD) δ: 8.17 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 8.6, 5.7 Hz, 1H), 6.66-6.79 (m, 1H), 4.83-4.90 (m, 1H), 3.56-3.71 (m, 1H), 2.94 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]⁻ 496, 498 253

1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 6.96- 7.18 (m, 1H), 6.73 (dd, J = 11.7, 8.8 Hz, 1H), 4.92-4.98 (m, 1H), 3.57-3.67 (m, 1H), 3.12 (s, 3H), 2.85 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]⁻ 510, 512 254

1H NMR (CD3OD) δ: 8.61 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 9.0, 4.9 Hz, 1H), 6.88 (dd, J = 11.2, 9.0 Hz, 1H), 4.91 (d, J = 11.0 Hz, 1H), 3.61-3.76 (m, 1H), 2.42 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.53 min, m/z [M − H]⁻ 546, 548 255

1H NMR (CD3OD) δ: 7.76-7.80 (m, 1H), 7.69-7.73 (m, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.3 Hz, 1H), 4.82 (d, J = 11.0 Hz, 1H), 3.51-3.65 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]⁻ 499, 501

TABLE 18-55 Example Structural Formula Physical Property Value 256

1H NMR (CD3OD) δ: 7.66 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.70 (dd, J = 11.5, 8.3 Hz, 1H), 4.92-5.00 (m, 1H), 3.67-3.79 (m, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H]⁻ 515, 517 257

1H NMR (CD3OD) δ: 7.73 (s, 1H), 7.61 (s, 1H), 6.98 (dd, J = 8.1, 5.9 Hz, 1H), 6.68-6.77 (m, 1H), 4.79-4.85 (m, 1H), 3.52-3.65 (m, 1H), 2.42 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]⁻ 495, 497 258

1H NMR (CD3OD) δ: 7.43 (dd, J = 10.3, 2.2 Hz, 1H), 7.30 (d, J = 1.1 Hz, 1H), 6.98 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7,8.3 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 3.60-3.75 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H]⁻ 499, 501 259

1H NMR (CD3OD) δ: 7.66 (s, 1H), 7.48 (s, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.72 (dd, J = 11.9, 8.3 Hz, 1H), 4.80-4.85 (m, 1H), 3.97 (s, 3H), 3.52-3.60 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.46-1.50 (m, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 511, 513 260

1H NMR (CD3OD) δ: 7.35 (s, 1H), 7.16 (s, 1H), 6.97 (dd, J = 8.5, 5.7 Hz, 1H), 6.72 (dd, J = 11.7, 8.5 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.47-3.56 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H]⁻ 507

TABLE 18-56 Example Structural Formula Physical Property Value 261

1H NMR (CD3OD) δ: 7.26 (s, 1H), 7.10 (s, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 12.1, 8.4 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.29-4.32 (m, 4H), 3.44-3.60 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 505 262

1H NMR (CD3OD) δ: 8.36 (s, 1H), 7.90 (s, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.73 (dd, J = 11.9, 8.3 Hz, 1H), 4.82-4.86 (m, 1H), 3.55-3.65 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]⁻ 526, 528 263

1H NMR (CD3OD) δ: 7.60(d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.21 (dd, J = 8.6, 2.7 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 6.20 (tt, J = 55.0, 3.7 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 4.31 (tdd, J = 13.6, 3.7, 2.6 Hz, 2H), 3.51-3.58 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.46 (d, J = 6.6 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]⁻ 527 264

1H NMR (CD3OD) δ: 8.51 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 8.8, 5.5 Hz, 1H), 6.77-6.91 (m, 1H), 4.89-4.95 (m, 1H), 3.65-3.75 (m, 1H), 2.48 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.54 min, m/z [M − H]⁻ 546, 548 265

1H NMR (CD3OD) δ: 8.10 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.75- 7.79 (m, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.39-7.45 (m, 2H), 7.20 (dd, J = 11.7, 9.2 Hz, 1H), 6.11-6.24 (m, 2H), 4.73 (d, J = 11.4 Hz, 1H), 4.12-4.30 (m, 1H), 3.85 (s, 3H), 1.62 (d, J = 6.6 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]⁻ 471

TABLE 18-57 Example Structural Formula Physical Property Value 266

1H NMR(CD3OD) δ: 7.37-7.45 (m, 2H), 6.94-7.08 (m, 2H), 6.85 (d, J = 6.6 Hz, 1H), 6.51-6.62 (m, 2H), 4.24 (d, J = 10.6 Hz, 1H), 3.36-3.48 (m, 1H), 2.59-2.75 (m, 4H), 1.59-1.85 (m, 4H), 1.29-1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]⁻ 427 267

1H NMR (CD3OD) δ: 7.52 (d, J = 9.2 Hz, 1H), 7.01 (s, 2H), 6.87-6.96 (m, 1H), 6.35-6.48 (m, 2H), 4.17 (d, J = 10.6 Hz, 1H), 3.20-3.35 (m, 1H), 2.75- 2.84 (m, 4H), 2.42 (s, 3H), 1.85-2.09 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]⁻ 427 268

1H NMR (CD3OD) δ: 8.82-8.91 (m, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.36-7.45 (m, 1H), 6.83-7.06 (m, 3H), 6.68 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 10.3 Hz, 1H), 3.34-3.46 (m, 1H), 2.72-2.82 (m, 4H), 1.81-2.10 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]⁻ 464 269

1H NMR (CD3OD) δ: 7.64 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 7.6, 1.9 Hz, 1H), 7.43-7.47 (m, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.21-7.27 (m, 2H), 6.12-6.16 (m, 2H), 4.59-4.66 (m, 1H), 4.26 (d, J = 10.9 Hz, 1H), 3.80 (s, 3H), 2.95 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]⁻ 467 270

1H NMR (CD3OD) 7.38 (d, J = 8.4 Hz, 1H), 6.98-7.07 (m, 2H), 6.91-6.95 (m, 1H), 6.20 (d, J = 1.8 Hz, 1H), 6.16 (dd, J = 8.6, 2.0 Hz, 1H), 4.57-4.63 (m, 1H), 4.21 (d, J = 11.0 Hz, 1H), 3.83 (s, 3H), 2.73-2.91 (m, 4H), 1.89-2.04 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H]⁻ 443

TABLE 18-58 Example Structural Formula Physical Property Value 271

LC/MS RT 1.75 min, m/z [M − H]⁻ 453, 455 272

LC/MS RT 1.8 min, m/z [M − H]⁻ 511, 513 273

1H NMR (CD3OD) δ: 7.46 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 6.98- 6.95 (1H, m), 6.71 (1H, dd, J = 11.9, 8.2 Hz), 4.79-4.66 (3H, m), 4.41-4.34 (1H, m), 4.24-4.18 (1H, m), 3.75-3.62 (3H, m), 2.19 (3H, s), 2.16 (3H, s), 1.49 (3H, d, J = 6.6 Hz); LC/MS RT 1.61 min, m/z [M − H]⁻ 553, 555 274

1H NMR (CD3OD) δ: 7.53 (d, J = 8.8 Hz, 1H), 6.96-7.04 (m, 1H), 6.71-6.81 (m, 2H), 6.55-6.60 (m, 1H), 4.66 (d, J = 11.4 Hz, 1H), 3.50-3.66 (m, 1H), 2.23 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H); LC/MS RT 1.92 min, m/z [M − H]⁻ 495, 497 275

1H-NMR (CDCl3) δ: 7.63 (1H, s), 7.10 (1H, d, J = 8.4 Hz), 6.94-6.88 (2H, m), 6.69 (1H, dd, J = 11.5, 8.6 Hz), 5.38 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.8 Hz), 4.41-4.40 (4H, m), 3.53-3.52 (2H, m), 2.18-2.17 (6H, m), 1.57-1.54 (3H, m).; LC/MS RT 1.71 min, m/z [M − H]⁻ 495, 497

TABLE 18-59 Example Structural Formula Physical Property Value 276

1H-NMR (CDCl3) δ: 8.07 (1H, br s), 7.64 (1H, d, J = 8.8 Hz), 7.07-7.06 (2H, m), 6.95-6.93 (1H, m), 6.38 (1H, d, J = 8.8 Hz), 5.68 (2H, s), 5.45 (1H, d, J = 10.4 Hz), 4.37 (1H, t, J = 10.4 Hz), 3.95 (3H, s), 3.88 (3H, s), 3.28-3.21 (1H, m), 2.88-2.83 (4H, m), 2.04-1.99 (2H, m), 1.49 (3H, d, J = 7.0 Hz).; LC/MS RT 1.67 min, m/z [M − H]⁻ 501 277

1H NMR (CD3OD) δ: 7.83 (d, J = 8.4 Hz, 1H), 7.58-7.60 (m, 1H), 7.55-7.57 (m, 1H), 6.94-7.02 (m, 1H), 6.67-6.77 (m, 1H), 4.76-4.82 (m, 1H), 3.57- 3.76 (m, 1H), 2.92 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.74 min, m/z [M − H]⁻ 495, 497 278

LC/MS RT 1.34 min, m/z [M − H]⁻ 509, 511 279

LC/MS RT 1.4 min, m/z [M − H]⁻ 493, 495 280

1H-NMR (CDCl3) δ: 8.12 (1H, br s), 7.15-7.13 (1H, m), 6.93-6.90 (1H, m), 6.75-6.64 (3H, m), 5.51 (1H, d, J = 10.6 Hz), 4.87 (1H, t, J = 10.6 Hz), 4.37- 4.35 (2H, m), 3.93 (1H, br s), 3.43-3.40 (3H, m), 2.19 (3H, s), 2.17 (3H, s), 1.54 (3H, d, J = 7.0 Hz).; LC/MS RT 1.6 min, m/z [M − H]⁻ 461

TABLE 18-60 Example Structural Formula Physical Property Value 281

1H NMR (CD3OD) δ: 7.90 (d, J = 1.0 Hz, 1H), 7.35-7.49 (m, 2H), 6.97 (t, J = 1.0 Hz, 1H), 6.73 (dd, J = 1.0 Hz, 1H), 4.70 (br d, J = 11.4 Hz, 1H), 4.28- 4.52 (m, 2H), 3.38-3.83 (m, 5H), 2.17 (s, 5H), 1.49 (d, J = 1.0 Hz, 3H); LC/MS RT 1.29 min, m/z [M − H]⁻ 459 282

LC/MS RT 1.94 min, m/z [M − H]⁻ 587, 589 283

1H NMR (CD3OD) δ: 7.94-7.99 (m, 1H), 7.84-7.91 (m, 1H), 6.81-6.93 (m, 1H), 6.61 (dd, J = 11.5, 8.6 Hz, 1H), 4.75 (d, J = 10.3 Hz, 1H), 3.37-3.89 (m, 5H), 2.88-3.03 (m, 1H), 2.24 (s, 3H), 2.14 (s, 3H), 1.75-1.85 (m, 1H), 1.36- 1.53 (m, 4H); LC/MS RT 1.25 min, m/z [M − H]⁻ 551, 553 284

1H-NMR (CDCl3) δ: 7.08 (1H, d, J = 8.8 Hz), 7.02-6.97 (3H, m), 6.88 (1H, d, J = 8.4 Hz), 5.42 (1H, d, J = 10.8 Hz), 4.56 (1H, t, J = 10.8 Hz), 4.47-4.36 (3H, m), 3.55-3.44 (3H, m), 2.24 (3H, s), 2.22 (3H, s), 2.17 (3H, s), 1.47 (3H, d, J = 7.0 Hz).; LC/MS RT 1.88 min, m/z [M − H]⁻ 519, 521 285

1H NMR (CD3OD) δ: 7.84-7.95 (m, 1H), 7.50-7.66 (m, 3H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.50-3.63 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.48 min, m/z [[M − H]⁻ 463

TABLE 18-61 Example Structural Formula Physical Property Value 286

1H NMR (CD3OD) δ: 7.87 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.2, 5.7 Hz, 1H), 6.72 (dd, J = 11.9, 8.2 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.53-3.63 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.59min, m/z [M − H]⁻ 497, 499 287

1H-NMR (CDCl3) δ: 8.70 (1H, s), 8.51-8.48 (1H, m), 7.87-7.84 (2H, m), 7.44 (1H, dd, J = 8.6, 2.1 Hz), 7.39 (1H, d, J = 2.1 Hz), 6.93 (1H, dd, J = 8.4, 5.9 Hz), 6.71-6.65 (2H, m), 4.87 (1H, t, J = 10.1 Hz), 3.53-3.48 (1H, m), 2.18-2.17 (6H, m), 1.43 (3H, d, J = 7.0 Hz).; LC/MS RT 1.72 min, m/z [M − H]⁻ 497, 499 288

LC/MS RT 1.76 min, m/z [M − H]⁻ 509, 511 289

LC/MS RT 1.8 min, m/z [M − H]⁻ 529, 531 290

1H NMR (CD3OD) δ: 7.73 (1H, d, J = 8.1 Hz), 7.16-7.15 (1H, m), 7.06-7.01 (2H, m), 6.71 (1H, dd, J = 10.6, 8.4 Hz), 5.38 (1H, d, J = 9.5 Hz), 4.68 (1H, d, J = 9.5 Hz), 3.96 (3H, s), 3.33 (1H, s), 2.25 (3H, s), 2.16 (3H, s); LC/MS RT 1.53 min, m/z [M − H]⁻ 470, 472

TABLE 18-62 Example Structural Formula Physical Property Value 291

LC/MS RT 1.75, 1.76 min, m/z [M − H]⁻ 472, 474 292

1H-NMR (CDCl3) δ: 7.98 (1H, d, J = 8.8 Hz), 7.94 (1H, s), 7.86-7.84 (1H, m), 7.78 (1H, d, J = 8.1 Hz), 7.72-7.70 (1H, m), 7.55 (1H, t, J = 7.7 Hz), 7.42 (1H, t, J = 7.3 Hz), 7.17-7.12 (1H, m), 7.08 (1H, d, J = 8.4 Hz), 5.79- 5.67 (1H, m), 5.62 (1H, d, J = 10.4 Hz), 4.94 (1H, t, J = 10.4 Hz), 4.60-4.56 (1H, m), 4.23-4.20 (1H, m), 3.99 (1H, s), 3.67-3.51 (1H, m), 2.38-2.35 (1H, m), 1.69 (3H, d, J = 5.9 Hz).; LC/MS RT 1.8 min, m/z [M − H]⁻ 534, 536 293

1H-NMR (CDCl3) δ: 8.56-8.54 (1H, m), 8.37-8.35 (1H, m), 8.10 (1H, s), 6.97-6.90 (1H, m), 6.71-6.64 (1H, m), 5.82 (1H, br s), 5.03-4.97 (1H, m), 3.54-3.52 (1H, m), 2.19-2.17 (6H, m), 1.53-1.44 (3H, m).; LC/MS RT 1.64 min, m/z [M − H]⁻ 535, 537 294

LC/MS RT 1.83 min, m/z [M − H]⁻ 510, 512 295

1H NMR (CD3OD) δ: 7.48 (d, J = 8.8 Hz, 1H), 6.91-7.03 (m, 4H), 6.70 (dt, J = 10.3, 2.0 Hz, 1H), 6.01 (dt, J = 10.3, 3.7 Hz, 1H), 4.98-5.04 (m, 2H), 4.33 (d, J = 10.6 Hz, 1H), 3.60-3.68 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]⁻ 474, 476

TABLE 18-63 Example Structural Formula Physical Property Value 296

LC/MS RT 1.73 min, m/z [M − H]⁻ 462, 464 297

1H NMR (CD3OD) δ: 7.69-7.80 (m, 1H), 7.30-7.40 (m, 1H), 6.93-7.06 (m, 1H), 6.69-6.82 (m, 1H), 5.38-5.49 (m, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 11.7 Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 4.02 (s, 3H), 3.68-3.75 (m, 1H), 2.86 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 1.64 (d, J = 6.6 Hz, 3H), 1.48 (d, J = 7.1 Hz, 3H); LC/MS RT 1.92 min, m/z [M − H]⁻ 556, 558 298

1H-NMR (CDCl3) δ: 7.81 (1H, d, J = 8.4 Hz), 7.06-6.88 (7H, m), 6.82 (1H, dd, J = 11.4, 8.4 Hz), 5.40 (1H, d, J = 10.4 Hz), 4.86 (1H, t, J = 10.4 Hz), 3.96 (3H, s), 3.83 (3H, s), 3.42 (1H, br s), 2.16 (3H, s), 1.59 (3H, d, J = 7.0 Hz); LC/MS RT 1.93 min, m/z [M − H]⁻ 560, 562 299

1H-NMR (CDCl3) δ: 7.89 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.04-6.98 (2H, m), 6.93 (1H, s), 6.88-6.75 (2H, m), 6.68-6.66 (2H, m), 5.44 (1H, d, J = 10.7 Hz), 4.85 (1H, t, J = 10.7 Hz), 3.96 (3H, s), 3.41 (1H, br s), 2.16 (3H, s), 1.59-1.57 (3H, m).; LC/MS RT 1.96 min, m/z [M − H]⁻ 566, 568 300

1H-NMR (CDCl3) δ: 8.57-8.55 (1H, m), 8.45-8.43 (1H, m), 7.82 (1H, d, J = 8.4 Hz), 7.64-7.61 (1H, m), 7.44-7.41 (1H, m), 7.05-7.00 (2H, m), 6.94- 6.88 (2H, m), 5.60-5.57 (1H, m), 4.82 (1H, t, J = 10.4 Hz), 3.96 (3H, s), 3.92 (1H, s), 3.46 (1H, s), 2.15 (3H, s), 1.61 (3H, d, J = 6.6 Hz).; LC/MS RT 1.4 min, m/z [M − H]⁻ 531, 533

TABLE 18-64 Example Structural Formula Physical Property Value 301

1H-NMR (CDCl3) δ: 7.82 (1H, d, J = 8.1 Hz), 7.59 (1H, s), 7.19-7.16 (1H, m), 7.02 (1H, d, J = 8.8 Hz), 6.92 (1H, s), 6.87-6.82 (1H, m), 6.28 (1H, s), 5.85 (1H, br s), 4.84 (1H, t, J = 10.1 Hz), 3.90 (3H, s), 3.45 (1H, br s), 2.24 (3H, s), 1.56 (3H, d, J = 6.6 Hz); LC/MS RT 1.56 min, m/z [M − H]⁻ 520, 522 302

1H-NMR (CDCl3) δ: 7.91 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.07-6.97 (4H, m), 6.86-6.81 (1H, m), 6.84 (1H, t, J = 9.9 Hz), 5.44 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 3.96 (3H, s), 3.41 (1H, br s), 2.14 (3H, s), 1.58 (3H, d, J = 7.0 Hz).; LC/MS RT 2.05 min, m/z [M − H]⁻ 564, 566 303

1H-NMR (CDCl3) δ: 7.81 (1H, d, J = 8.4 Hz), 7.52-7.51 (2H, m), 7.09-6.99 (4H, m), 6.93-6.93 (1H, m), 6.85-6.80 (1H, m), 5.49-5.46 (1H, m), 4.88- 4.83 (1H, m), 3.96 (3H, s), 3.43 (1H, br s), 2.27 (3H, s), 1.58 (3H, d, J = 7.0 Hz).; LC/MS RT 1.54 min, m/z [M − H]⁻ 520, 522 304

1H-NMR (CDCl3) δ: 8.06 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.73 (1H, s), 7.59 (1H, s), 7.57-7.54 (1H, m), 7.41-7.36 (1H, m), 7.03-7.00 (1H, m), 6.93-6.92 (1H, m), 6.84 (1H, dd, J = 11.0, 8.4 Hz), 5.45 (1H, d, J = 10.4 Hz), 4.86 (1H, t, J = 10.4 Hz), 3.96 (3H, s), 3.44 (1H, br s), 2.27 (3H, s), 1.58 (3H, d, J = 9.5 Hz).; LC/MS RT 1.75 min, m/z [M − H]⁻ 570, 572 305

1H-NMR (CDCl3) δ: 8.81 (1H, br s), 7.80 (1H, d, J = 8.8 Hz), 7.36 (1H, s), 7.23-7.20 (1H, m), 7.01 (1H, d, J = 8.4 Hz), 6.93 (1H, s), 6.82 (1H, t, J = 9.7 Hz), 6.19 (1H, s), 5.50 (1H, d, J = 10.4 Hz), 4.86 (1H, t, J = 10.4 Hz), 3.95 (3H, s), 3.90 (3H, s), 3.45 (1H, br s), 2.30 (3H, s), 1.56 (3H, d, J = 6.6 Hz).; LC/MS RT 1.64 min, m/z [M − H]⁻ 534, 536

TABLE 18-65 Example Structural Formula Physical Property Value 306

1H-NMR (CDCl3) δ: 8.48 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.39 (1H, s), 7.28 (1H, s), 7.06-6.99 (2H, m), 6.92-6.92 (1H, m), 6.80 (1H, dd, J = 11.2, 8.6 Hz), 5.56 (1H, d, J = 10.6 Hz), 4.84 (1H, t, J = 10.6 Hz), 3.94 (3H, s), 3.91 (3H, s), 3.44 (1H, s), 2.27 (3H, s), 1.57 (3H, d, J = 7.0 Hz).; LC/MS RT 1.62 min, m/z [M − H]⁻ 534, 536 307

LC/MS RT 1.65 min, m/z [M − H]⁻ 534, 536 308

LC/MS RT 1.82 min, m/z [M − H]⁻ 534, 536 309

LC/MS RT 1.94 min, m/z [M − H]⁻ 597, 599 310

1H-NMR (CDCl3) δ: 8.50 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.40 (1H, s), 7.32 (1H, s), 7.05 (1H, dd, J = 8.5, 5.9 Hz), 7.01 (1H, dd, J = 8.4, 1.5 Hz), 6.92 (1H, d, J = 1.8 Hz), 6.80 (1H, dd, J = 11.2, 8.5 Hz), 5.56 (1H, d, J = 10.3 Hz), 4.85 (1H, t, J = 10.8 Hz), 4.18 (2H, q, J = 7.3 Hz), 3.94 (3H, s), 3.44 (1H, br s), 2.28 (3H, s), 1.57 (3H, d, J = 7.0 Hz), 1.50 (3H, t, J = 7.3 Hz).; LC/MS RT 1.68 min, m/z [M − H]⁻ 548, 550

TABLE 18-66 Example Structural Formula Physical Property Value 311

LC/MS RT 1.71 min, m/z [M − H]⁻ 560, 562 312

1H-NMR (CDCl3) δ: 7.80 (1H, d, J = 8.4 Hz), 7.42 (1H, s), 7.36 (1H, s), 7.06-6.99 (2H, m), 6.92 (1H, s), 6.82-6.77 (1H, m), 5.53 (1H, d, J = 10.7 Hz), 4.85 (1H, t, J = 10.7 Hz), 4.75 (1H, t, J = 8.4 Hz), 3.94 (3H, s), 3.44 (1H, br s), 2.55-2.46 (4H, m), 2.28 (3H, s), 1.89- 1.82 (2H, m), 1.56 (3H, d, J = 7.0 Hz); LC/MS RT 1.8 min, m/z [M − H]⁻ 574, 576 313

1H-NMR (CDCl3) δ: 8.20 (1H, d, J = 2.0 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.47- 7.44 (1H, m), 7.35 (1H, d, J = 8.4 Hz), 7.05- 7.02 (1H, m), 7.01-6.99 (1H, m), 6.94 (1H, d, J = 2.0 Hz), 6.92-6.87 (1H, m), 5.43 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 3.96 (3H, s), 3.42 (1H, br s), 2.16 (3H, s), 1.59 (3H, d, J = 7.0 Hz); LC/MS RT 1.82 min, m/z [M − H]⁻ 565, 567 314

1H-NMR (CDCl3) δ: 8.94 (1H, br s), 7.91 (1H, d, J = 2.0 Hz), 7.80 (1H, d, J = 8.4 Hz), 7.39-7.36 (1H, m), 7.01-6.97 (2H, m), 6.93 (1H, d, J = 1.0 Hz), 6.85 (1H, dd, J = 11.4, 8.4 Hz), 6.76 (1H, d, J = 8.4 Hz), 5.60 (1H, d, J = 10.4 Hz), 4.84 (1H, t, J = 10.4 Hz), 3.94 (3H, s), 3.93 (3H, s), 3.44 (1H, br s), 2.16 (3H, s), 1.58 (3H, d, J = 7.0 Hz).; LC/MS RT 1.82 min, m/z [M − H]⁻ 561, 563 315

1H-NMR (CDCl3) δ: 7.95 (1H, d, J = 2.0 Hz), 7.79 (1H, d, J = 8.5 Hz), 7.32 (1H, dd, J = 8.5, 2.4 Hz), 7.00-6.95 (2H, m), 6.92 (1H, d, J = 2.0 Hz), 6.83 (1H, dd, J = 11.2, 8.7 Hz), 6.65 (1H, d, J = 8.7 Hz), 5.61 (1H, d, J = 10.5 Hz), 4.84 (1H, t, J = 10.5 Hz), 3.93 (3H, s), 3.84-3.80 (4H, m), 3.51-3.44 (5H, m), 2.17 (3H, s), 1.57 (3H, d, J = 7.0 Hz); LC/MS RT 1.48 min, m/z [M − H]⁻ 616, 618

TABLE 18-67 Example Structural Formula Physical Property Value 316

1H NMR (CD3OD) δ: 8.53 (1H, s), 7.74 (1H, d, J = 8.4 Hz), 7.61 (1H, s), 7.12-7.09 (1H, m), 7.05-6.98 (2H, m), 6.88-6.83 (1H, m), 4.70-4.60 (2H, m), 3.94 (3H, s), 2.08 (3H, s), 1.52 (3H, d, J = 7.0 Hz); LC/MS RT 1.68 min, m/z [M − H]⁻ 588, 590 317

1H NMR (CD3OD) δ: 8.27 (1H, br s), 7.75 (1H, d, J = 8.4 Hz), 7.34 (1H, s), 7.12 (1H, d, J = 1.8 Hz), 7.04 (1H, dd, J = 8.4, 1.8 Hz), 6.96 (1H, dd, J = 8.4, 5.9 Hz), 6.84 (1H, dd, J = 11.4, 8.4 Hz), 4.68 (1H, d, J = 11.4 Hz), 3.94 (3H, s), 3.82 (3H, s), 3.67-3.62 (1H, m), 2.13 (3H, s), 1.88 (3H, s), 1.52 (3H, d, J = 7.0 Hz); LC/MS RT 1.63 min, m/z [M − H]⁻ 548, 550 318

1H-NMR (CDCl3) δ: 9.20 (1H, s), 8.60 (2H, s), 8.02 (1H, br s), 7.82 (1H, d, J = 8.1 Hz), 7.05-7.03 (2H, m), 6.97-6.92 (2H, m), 5.53 (1H, d, J = 11.1 Hz), 4.87 (1H, t, J = 11.1 Hz), 3.96 (3H, s), 3.45 (1H, br s), 2.20 (3H, s), 1.61 (3H, d, J = 7.0 Hz).; LC/MS RT 1.55 min, m/z [M − H]⁻ 532, 534 319

1H-NMR (CDCl3) δ: 8.34 (2H, s), 7.81 (1H, d, J = 8.4 Hz), 7.03-6.88 (4H, m), 5.57 (1H, d, J = 10.6 Hz), 4.85 (1H, t, J = 10.6 Hz), 4.04 (3H, s), 3.95 (3H, s), 3.44 (1H, br s), 2.18 (3H, s), 1.59 (3H, d, J = 7.0 Hz); LC/MS RT 1.66 min, m/z [M − H]⁻ 562, 564 320

1H-NMR (CDCl3) δ: 8.12 (1H, br s), 7.99 (1H, s), 7.80 (1H, d, J = 7.7 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.03-6.93 (3H, m), 6.87-6.81 (1H, m), 6.72 (1H, d, J = 8.4 Hz), 5.52 (1H, d, J = 10.6 Hz), 4.79 (1H, t, J = 10.6 Hz), 3.94 (3H, s), 3.57-3.55 (4H, m), 3.45 (1H, br s), 2.17 (3H, s), 1.69-1.66 (6H, m), 1.59 (3H, d, J = 6.6 Hz).; LC/MS RT 1.49 min, m/z [M − H]⁻ 614, 616

TABLE 18-68 Example Structural Formula Physical Property Value 321

1H-NMR (CDCl3) δ: 8.19-8.08 (2H, m), 7.80 (1H, d, J = 8.4 Hz), 7.37-7.27 (1H, m), 7.02 (1H, d, J = 8.4 Hz), 6.95-6.92 (2H, m), 6.88-6.83 (1H, m), 5.50 (1H, d, J = 10.3 Hz), 4.83 (1H, t, J = 11.0 Hz), 3.95-3.94 (3H, m), 3.77 (3H, s), 3.42 (1H, br s), 2.04-2.03 (3H, m), 1.58 (3H, d, J = 6.6 Hz).; LC/MS RT 1.96 min, m/z [M − H]⁻ 595, 597 322

1H-NMR (CDCl3) δ: 8.08-8.05 (2H, m), 7.80 (1H, d, J = 8.1 Hz), 7.53 (1H, s), 7.02-6.93 (2H, m), 6.85-6.81 (2H, m), 5.55 (1H, d, J = 10.9 Hz), 4.80 (1H, t, J = 10.9 Hz), 4.28-4.25 (2H, m), 3.94 (3H, s), 3.51 (2H, s), 3.44 (1H, br s), 3.14 (3H, s), 2.17 (3H, s), 1.59 (3H, d, J = 6.2 Hz).; LC/MS RT 1.44 min, m/z [M − H]⁻ 602, 604 323

1H NMR (CD3OD) δ: 8.60 (1H, s), 8.45 (1H, s), 7.76 (1H, d, J = 8.4 Hz), 7.68 (1H, s), 7.14-7.10 (2H, m), 7.05 (1H, dd, J = 8.4, 1.8 Hz), 6.97 (1H, dd, J = 11.2, 8.4 Hz), 4.70 (1H, d, J = 11.2 Hz), 3.94 (3H, s), 3.77-3.74 (4H, m), 3.69-3.63 (4H, m), 3.48-3.46 (1H, m), 2.20 (3H, s), 1.55 (3H, d, J = 7.0 Hz); LC/MS RT 1.52 min, m/z [M − H]⁻ 644, 646 324

1H-NMR (CDCl3) δ: 7.96 (1H, d, J = 8.1 Hz), 7.55-7.51 (2H, m), 7.40 (1H, s), 7.28 (1H, s), 7.04 (1H, dd, J = 8.4, 5.9 Hz), 6.84-6.79 (2H, m), 6.05-6.03 (1H, m), 5.98-5.96 (1H, m), 4.95-4.90 (1H, m), 3.92 (3H, s), 3.50 (1H, br s), 2.28 (3H, s), 1.49 (3H, d, J = 7.3 Hz); LC/MS RT 1.46 min, m/z [M − H]⁻ 547, 549 325

1H-NMR (CDCl3) δ: 9.65 (1H, br s), 7.81-7.79 (2H, m), 7.74 (1H, s), 7.60- 7.59 (1H, m), 7.50-7.48 (1H, m), 6.95-6.91 (1H, m), 6.73-6.68 (1H, m), 6.20 (1H, d, J = 10.0 Hz), 4.90 (1H, t, J = 10.0 Hz), 3.92 (3H, s), 3.47 (1H, br s), 2.15 (3H, s), 2.13 (3H, s), 1.50 (3H, d, J = 6.6 Hz).; LC/MS RT 1.69 min, m/z [M − H]⁻ 518, 520

TABLE 18-69 Example Structural Formula Physical Property Value 326

1H-NMR (CDCl3) δ: 7.81-7.79 (2H, m), 7.76 (1H, dd, J = 8.5, 2.2 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.46-7.42 (1H, m), 7.31- 7.28 (2H, m), 7.17 (1H, t, J = 8.8 Hz), 6.97-6.93 (1H, m), 6.71 (1H, dd, J = 11.7, 8.3 Hz), 5.05 (1H, d, J = 10.0 Hz), 4.85 (1H, t, J = 10.0 Hz), 3.43 (1H, br s), 2.18 (3H, s), 2.16 (3H, s), 1.47 (3H, d, J = 5.9 Hz).; LC/MS RT 1.96 min, m/z [M − H]⁻ 532, 534 327

1H-NMR (CDCl3) δ: 7.80 (1H, d, J = 8.1 Hz), 7.50-7.47 (2H, m), 7.36-7.33 (5H, m), 7.02 (1H, dd, J = 8.4, 1.8 Hz), 6.93 (1H, d, J = 1.5 Hz), 6.81 (1H, dd, J = 11.4, 8.4 Hz), 5.41 (1H, d, J = 10.5 Hz), 4.82 (1H, t, J = 10.5 Hz), 3.97 (3H, s), 3.42 (1H, br s), 2.51 (3H, s), 1.57-1.54 (3H, m).; LC/MS RT 2.06 min, m/z [M − H]⁻ 554, 556 328

1H NMR (CD3OD) δ: 8.34 (1H, br s), 7.76-7.65 (1H, m), 7.25-7.22 (1H, m), 7.17-7.09 (1H, m), 6.90-6.85 (1H, m), 4.79-4.70 (2H, m), 4.59-4.51 (2H, m); 4.41-4.26 (2H, m); 3.72-3.66 (1H, m), 2.38- 2.37 (6H, m), 2.33-2.23 (2H, m), 1.86 (3H; d, J = 28.2 Hz).; LC/MS RT 1.39 mm, m/z [M − H]⁻ 543, 545 329

1H NMR (CD3OD) δ: 7.68-7.79 (m, 1H), 7.42-7.46 (m, 1H), 7.12-7.20 (m, 1H), 6.79-6.88 (m, 1H), 4.71-4.82 (m, 1H), 4.54-4.65 (m, 1H), 4.25-4.46 (m, 1H), 3.63-3.77 (m, 1H), 2.44 (s, 3H), 2.32-2.38 (m, 2H), 1.89-1.94 (m, 3H), 1.51-1.56 (m, 3H); LC/MS RT 1.39 min, m/z [M − H]⁻ 587, 589 330A

LC/MS RT 1.37 min, m/z [M − H]⁻ 543, 545

TABLE 18-70 Example Structural Formula Physical Property Value 330B

LC/MS RT 1.37 min, m/z [M − H]⁻ 543, 545 331

1H-NMR (CDCl3) δ: 8.54 (2H, s), 8.42 (1H, s), 8.32-8.30 (1H, m), 7.75 (1H, d, J = 8.1 Hz), 6.96-6.88 (2H, m), 6.67 (1H, dd, J = 11.4, 8.4 Hz), 6.30 (1H, s), 6.10 (1H, s), 4.97 (1H, t, J = 10.3 Hz), 3.48 (1H, s), 2.16 (3H, s), 2.15 (3H, s), 1.48 (3H, d, J = 7.0 Hz).; LC/MS RT 1.5 min, m/z [M − H]⁻ 515 332

1H NMR (CD3OD) δ: 7.68-7.79 (m, 3H), 6.97 (dd, J = 8.5, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.5 Hz, 1H), 4.89-5.02 (m, 1H), 3.58-3.65 (m, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.47 (d, J = 7.3 Hz, 3H); LC/MS RT 1.75 min, m/z [M − H]⁻ 541, 543 333

1H NMR (CD3OD) δ: 7.73 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.81- 6.99 (m, 3H), 4.15 (d, J = 6.2 Hz, 1H), 3.98 (s, 3H), 3.38-3.43 (m, 1H), 2.75- 2.92 (m, 4H), 1.92-2.13 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H); LC/MS RT 1.95 min, m/z [M − H]⁻ 540, 542 334

LC/MS RT 1.89 min, m/z [M − H]⁻ 506, 508

TABLE 18-71 Example Structural Formula Physical Property Value 335

1H NMR (CD3OD) δ: 7.65-7.74 (m, 2H), 7.57-7.64 (m, 1H), 7.50 (d, J = 3.3 Hz, 1H), 6.98-7.18 (m, 2H), 6.79-6.84 (m, 1H), 3.99 (d, J = 9.9 Hz, 1H), 3.40- 3.50 (m 1H), 2.70-2.86 (m, 1H), 2.57-2.66 (m, 1H), 2.32-2.51 (m, 2H), 1.82 (s, 3H), 1.45-1.54 (m, 2H), 1.44 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H); LC/MS RT 2.11 min, m/z [M − H]⁻ 534, 536 336

1H NMR (CD3OD) δ: 8.02 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 6.97- 6.99 (m, 3H), 6.88-6.90 (m, 1H), 4.31 (d, J = 10.3 Hz, 1H), 3.34-3.46 (m, 1H), 2.71-2.97 (m, 4H), 2.14 (s, 6H), 1.93- 2.02 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.87 min, m/z [M − H]⁻ 506, 508 337

1H NMR (CD3OD) : 7.93 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 8.1, 5.9 Hz, 1H), 6.76 (dd, J = 11.9, 8.6 Hz, 1H), 5.58 (dd, J = 11.7,1.8 Hz, 1H), 3.76-3.90 (m, 1H), 3.06 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]⁻495, 497 338

1H-NMR (CDCl3) δ: 8.15 (1H, s), 7.86 (1H, d, J = 8.4 Hz), 7.52 (1H, dd, J = 8.4, 1.5 Hz), 7.48-7.47 (1H, m), 6.94 (1H, dd, J = 8.2, 5.7 Hz), 6.69 (1H, dd, J = 11.7, 8.4 Hz), 5.33 (1H, d, J = 9.9 Hz), 4.85 (1H, t, J = 10.3 Hz), 3.50- 3.45 (1H, m), 2.18 (6H, s), 1.47 (3H, d, J = 7.0 Hz).; LC/MS RT 1.95 min, m/ [M − H]− 566, 568 339

1H-NMR (CDCl3) δ: 7.97 (1H, s), 7.64-7.61 (1H, m), 7.40 (1H, dd, J = 8.8, 5.1 Hz), 6.96 (1H, dd, J = 8.1, 5.9 Hz), 6.70 (1H, dd, J = 11.4, 8.4 Hz), 5.40 (1H, d, J = 9.2 Hz), 4.89 (1H, t, J = 9.3 Hz), 3.52-3.47 (1H, m), 2.19 (6H, s), 1.48 (3H, d, J = 7.3 Hz).; LC/MS RT 1.86 min, m/ [M − H]− 519, 521

TABLE 18-72 Example Structural Formula Physical Property Value 340

1H-NMR (CDCl3) δ: 8.31-8.28 (2H, m), 8.13 (1H,s), 8.02-7.98 (2H, m), 6.95 (1H, dd, J = 8.4, 5.9 Hz), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 5.32-5.29 (1H, m), 4.87 (1H, t, J = 9.9 Hz), 3.48-3.44 (1H, m), 2.17 (3H, s), 2.16 (3H, s), 1.43 (3H, d, J = 7.0 Hz).; LC/MS RT 1.73 min, m/ [M − H]− 449 341

1H-NMR (CDCl3) δ: 8.42 (1H, s), 7.94-7.92 (2H, m), 7.77-7.75 (2H, m), 6.95 (1H, dd, J = 8.4, 5.9 Hz), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 5.45 (1H, d, J = 9.5 Hz), 4.84 (1H, t, J = 9.7 Hz), 3.48-3.42 (1H, m), 2.18 (3H, s), 2.15 (3H, s), 1.42 (3H, d, J = 7.0 Hz).; LC/MS RT 1.67 min, m/ [M − H]− 429 342

1H-NMR (CDCl3) δ: 8.62 (1H, br s), 7.98 (1H, d, J = 8.1 Hz), 7.33 (1H, dd, J = 8.1, 1.1 Hz), 7.20 (1H, d, J = 1.1 Hz), 6.93 (1H, dd, J = 8.4, 5.9 Hz), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 5.55 (1H, d, J = 10.3 Hz), 4.84 (1H, t, J = 10.6 Hz), 4.01 (3H, s), 3.43 (1H, br s), 2.17 (6H, s), 1.52 (3H, d, J = 7.0 Hz).; LC/MS RT 1.71 min, m/ [M − H]−459, 461 343

1H-NMR (CD3OD) δ: 8.25 (1H, s), 8.09 (1H, d, J = 2.2 Hz), 7.95-7.86 (2H, m), 7.00-6.96 (1H, m), 6.72 (1H, dd, J = 11.5, 8.2 Hz), 4.74 (1H, d, J = 11.4 Hz), 3.57-3.54 (1H, m), 2.18 (3H, s), 2.17 (3H, s), 1.45 (3H, d, J = 7.0 Hz).; LC/MS RT 1.78 min, m/ [M − H]− 507, 509

TABLE 18-73 Example Structural Formula Physical Property Value 344

1H-NMR (CDCl3) δ: 7.98 (1H, s), 7.77 (1H, d, J = 2.6 Hz), 7.65 (1H, dd, J = 8.4, 2.6 Hz), 7.52 (1H, d, J = 8.4 Hz), 7.36-7.34 (2H, m), 6.99-6.92 (4H, m), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 5.11 (1H, d, J = 10.0 Hz), 4.85 (1H, t, J = 10.1 Hz), 3.85 (3H, s), 3.43-3.41 (1H, m), 2.17 (3H, s), 2.15 (3H, s), 1.45 (3H, d, J = 6.2 Hz).; LC/MS RT 1.97 min, m/ [M − H]− 544, 546 345

1H-NMR (CDCl3) δ: 8.08 (1H, d, J = 1.8 Hz), 7.71 (2H, dd, J = 7.9, 1.6 Hz), 7.60 (1H, d, J = 8.1 Hz), 7.39-7.35 (1H, m), 7.28-7.26 (2H, m), 7.19 (1H, d, J = 10.3 Hz), 7.07-7.03 (1H, m), 7.00-6.98 (1H, m), 6.89 (1H, dd, J = 8.4, 5.9 Hz), 6.67 (1H, dd, J = 11.4, 8.4 Hz), 6.06 (1H, s), 5.90 (1H, s), 4.95 (1H, t, J = 10.6 Hz), 3.85 (3H, s), 3.46-3.44 (1H, m), 2.16 (3H, s), 2.15 (3H, s), 1.50 (3H, d, J = 7.0 Hz).; LC/MS RT 1.8 min, m/ [M − H]− 553, 555 346

1H-NMR (CDCl3) δ: 10.58 (1H, s), 7.93 (1H, d, J = 8.4 Hz), 7.36-7.34 (2H, m), 6.91 (1H, dd, J = 8.2, 5.7 Hz), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 6.44 (2H, s), 5.56 (1H, d, J = 10.3 Hz), 4.84 (1H, t, J = 11.0 Hz), 4.02 (3H, s), 3.42 (1H, br s), 2.17-2.16 (6H, m), 1.56 (3H, d, J = 7.0 Hz).; LC/MS RT 1.51 min, m/ [M − H]− 477 347

1H-NMR (CD3OD) δ: 7.96-7.93 (2H, m), 7.86-7.83 (2H, m), 6.96 (1H, dd, J = 8.4, 5.9 Hz), 6.71 (1H, dd, J = 11.7, 8.4 Hz), 4.74 (1H, d, J = 11.0 Hz), 3.57-3.53 (1H, m), 2.17 (3H, s), 2.15 (3H, s), 1.42 (3H, d, J = 7.0 Hz).; LC/MS RT 1.46 min, m/ [M − H]−447

TABLE 18-74 Example Structural Formula Physical Property Value 348

LC/MS RT min, m/ [M − H]− 486, 488 349

1H-NMR (CDCl3) δ: 7.80 (1H, d, J = 8.4 Hz), 7.05 (1H, dd, J = 8.4, 1.8 Hz), 6.96-6.93 (2H, m), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 5.96 (1H, d, J = 9.9 Hz), 4.78 (1H, t, J = 9.7 Hz), 3.91 (3H, s), 3.54-3.49 (1H, m), 2.17 (3H, s), 2.13 (3H, s), 2.49 (3H, d, J = 7.0 Hz).; LC/MS RT 1.77 min, m/ [M − H]− 468, 470 350

1H-NMR (CDCl3) δ: 11.70 (1H, s), 11.48 (1H, s), 7.75 (1H, d, J = 8.4 Hz), 6.92-6.89 (2H, m), 6.73-6.68 (1H, m), 6.62 (1H, d, J = 8.4 Hz), 6.16 (1H, d, J = 9.2 Hz), 4.89 (1H, t, J = 10.3 Hz), 3.85 (3H, s), 3.60-3.58 (1H, m), 2.16 (3H, s), 2.13 (3H, s), 1.47 (3H, d, J = 6.6 Hz).; LC/MS RT 1.6 min, m/ [M − H]− 483, 485

Test Example

The compound according to the present invention was evaluated using the following test method.

Test Example 1 Human RNR Inhibition Effect

The inhibitory activity against the ribonucleotide reduction reaction (hereinafter referred to as RNR reaction) of the test compound was determined by measuring the formation of deoxycytidine diphosphate (hereinafter referred to as dCDP) from cytidine diphosphate (hereinafter referred to as CDP) by the following method.

Human M1 subunit and human M2 subunit (mutant lacking amino terminal 59 amino acids), which are fused a histidine tag at the amino terminus, are overexpressed in Escherichia coli and are solubilized after collection, and histidine tagged human M1 and M2 proteins were purified on a nickel chelate column.

For measuring the inhibitory activity of the test compound against the RNR reaction, the method described in the document [CANCER RESEARCH 64, 1-6, 2004] was referred to.

First, test compounds were serially diluted with DMSO. Next, human M1 protein and human M2 protein were added to an aqueous albumin solution derived from 0.02% fetal bovine serum, a DMSO solution of the compound of the present invention or the control DMSO solution (final concentration of DMSO was 1%) was added, and the mixture was allowed to stand for 20 minutes. Thereafter, the reaction buffer [50 mM HEPES buffer (pH 7.2) at the final concentration, 4 mM magnesium acetate at the final concentration, 100 mM potassium chloride at the final concentration, 6 mM dithiothreitol at the final concentration, 2 mM adenosine triphosphate at the final concentration, 0.24 mM nicotinamide adenine dinucleotide phosphate at final concentration] and 10 μM CDP at the final concentration were added and incubated at 37° C. for 30 minutes to perform RNR reaction. Immediately after the reaction, the reaction was stopped by heating at 100° C. for 15 minutes, followed by centrifugation at 10,000 rpm for 10 minutes. After the centrifugation, a portion (5 μL) of the resulting supernatant was analyzed with a high performance liquid chromatography (Shimadzu Corporation, Prominence) using Shim-pack XR-ODS (manufactured by Shimadzu GLC Co., 3.0×100 mm). Elution was carried out at a measurement wavelength of 265 nm at a flow rate of 0.5 mL/min by a 9-minute concentration gradient from the 12:13 mixture of mobile phase A (10 mM potassium dihydrogen phosphate (pH 6.7), 10 mM tetrabutylammonium, 0.25% methanol) and mobile phase B (50 mM potassium dihydrogen phosphate (pH 6.7), 5.6 mM tetrabutylammonium, 30% methanol) to the same 2:3 mixture to measure the substrate CDP (RT 5.9 min) and the reaction product dCDP (RT 6.2 min).

The inhibitory activity of the test compound was determined by the following equation, and the concentrations of test compounds inhibiting the RNR reaction by 50% are shown as IC₅₀ (M) in Tables 19-1 to 19-3.

[Mathematical  Formula  1]                      ${{Inhibition}\mspace{14mu}{rate}\mspace{14mu}(\%)} = {\left( {1 - \frac{\begin{matrix} {{Amount}\mspace{14mu}{of}\mspace{14mu}{produced}\mspace{14mu}{dCDP}} \\ {{where}\mspace{14mu}{test}\mspace{14mu}{compounded}\mspace{14mu}{added}} \\ ({pmol}) \end{matrix}}{\begin{matrix} {{Amount}\mspace{14mu}{of}\mspace{14mu}{produced}\mspace{14mu}{dCDP}\mspace{14mu}{of}\mspace{14mu}{control}} \\ ({pmol}) \end{matrix}}} \right) \times 100}$

As a result, it is apparent from the following table that the compound of the present invention has an excellent RNR inhibitory action. In contrast, the compound of Comparative Example 1 had an IC₅₀ of 43 μM, and showed no inhibitory activity against RNR as found in the example compounds of the present invention.

TABLE 19-1 RNR Enzyme inhibitory Example activity Number IC₅₀ (μM) 1 0.06 3 0.30 4 0.38 5 0.14 6 0.11 7 0.45 9 0.60 10 0.14 11 0.18 12 0.17 13 0.14 14 0.25 15 0.10 16 0.13 17 0.50 18 0.13 19 0.19 20 0.26 21 0.24 22 0.34 23 0.74 25 0.15 26 0.16 27 0.55 28 0.50 30 0.15 31 0.10 32 0.79 35 0.13 36 0.11 37 0.14 38 0.19 39 0.04 40 0.13 41 0.10 42 0.20 43 0.08 46 0.84 48 0.60 49 0.80 50 0.85 52 0.77 60 0.99 67 0.70 71 0.24 76 0.20 81 0.28 83 0.14 84 0.36 85 0.84 86 0.40 87 0.84 88 0.15 89 0.42 90 0.16 91 0.23 92 0.20 93 0.10 94 0.11 95 0.14 96 0.10 97 0.24 98 0.64 99 0.29 100 0.30 101 0.13 102 0.14 103 0.41 104 0.84 105 0.16 106 0.27 107 0.24 108 0.43 109 0.06 110 0.96 111 0.27 112 0.15 113 0.06 114 0.06 115 0.18 116 0.07 117 0.03 118 0.34 119 0.45 120 0.43 123 0.11 124 0.09 129 0.10 137 0.59 142 0.21 144 0.17 145 0.44 146 0.26 147 0.27 148 0.10 151 0.41 152 0.71 153 0.11 155 0.13 156 0.08 157 0.10 158 0.45 159 0.16 161 0.28 162 0.74 164 0.33 165 0.83 167 0.08 169 0.19 171 0.47 172 0.82 173 0.13 174 0.35 176 0.81 178 0.17 179 0.28 181 0.66 182 0.41 183 0.32 184 0.22 185 0.60 186 0.09 188 0.64 189 0.55 192 0.44 193 0.09 194 0.36 195 0.18

TABLE 19-2 RNR Enzyme inhibitory Example activity Number IC₅₀ (μM) 196 0.08 197 0.06 198 0.06 199 0.35 200A 0.03 200B 0.08 201 0.17 202 0.40 203 0.18 204 0.15 205 0.08 206A 0.15 207A 0.13 207B 0.09 208A 0.10 208B 0.06 209A 0.10 209B 0.18 210 0.18 211A 0.12 212 0.11 213 0.50 214 0.99 215 0.19 216 0.20 217 0.96 219 0.27 220A 0.06 220B 0.08 222A 0.08 222B 0.06 223 0.79 224A 0.09 224B 0.10 225A 0.12 226A 0.05 226B 0.07 227A 0.05 227B 0.09 228A 0.08 228B 0.14 229A 0.06 229B 0.11 230A 0.12 230B 0.05 231 0.65 232 0.23 233 0.13 234A 0.31 235A 0.08 235B 0.07 236 0.38 237A 0.29 238A 0.11 239A 0.20 240 0.91 241 0.14 242 0.23 243A 0.07 243B 0.10 244A 0.09 244B 0.22 245 0.04 246 0.50 247 0.41 248 0.27 249 0.10 250 0.02 251 0.25 252 0.06 253 0.08 254 0.07 255 0.12 256 0.42 257 0.10 258 0.14 259 0.10 260 0.36 261 0.09 262 0.13 263 0.07 264 0.06 265 0.26 266 0.85 269 0.51 270 0.73 271 0.23 272 0.66 273 0.13 274 0.44 275 0.10 277 0.37 278 0.13 280 0.42 281 0.76 282 0.91 283 0.15 284 0.56 285 0.31 286 0.07 287 0.05 288 0.06 289 0.13 290 0.84 292 0.16 294 0.11 295 0.79 298 0.30 299 0.94 300 0.34 301 0.29 302 0.49 303 0.16 304 0.16 305 0.24 306 0.09 308 0.18 310 0.17 311 0.22 312 0.22 313 0.34 314 0.26 315 0.19 317 0.28 318 0.54 319 0.28 320 0.60 322 0.22

TABLE 19-3 RNR Enzyme inhibitory Example activity Number IC₅₀ (μM) 323 0.42 324 0.17 325 0.22 328 0.11 329 0.06 330A 0.12 330B 0.46 331 0.09 332 0.13 333 0.31 334 0.83 337 0.08 338 0.10 339 0.51 340 0.27 341 0.41 342 0.09 343 0.64 344 0.72 345 0.25 346 0.42 349 0.25 350 0.46

Test Example 2 Cell Proliferation Inhibitory Effect on Human Breast Cancer Cell Line

Human derived breast cancer cell line HCC 1806 cells were daily passaged at a cell density not exceeding 80% in ATCC recommended Roswell Park Memorial Institute medium (RPMI-1640) containing 10% fetal bovine serum (FBS). In order to start the test of cell proliferation inhibitory activity, HCC 1806 cells were suspended in the above medium, after seeing at 180 μL in each well of a 96-well flat bottom plate so that the number of cells per well was 2,000, the cells were cultured at 37° C. for 1 day in an incubator containing 5% carbon dioxide gas. On the next day, the test compound was dissolved in DMSO, and 20 μL of a drug additive solution diluted serially with distilled water to 10 times of the final concentration was added to each well of the culture plate of the cells, and the cells were cultured at 37° C. for 72 hours in an incubator containing 5% carbon dioxide gas. After culturing for 72 hours, 20 μL of glutaraldehyde was added to each well and allowed to stand for 30 minutes, then the plate was washed 10 times with water and was dried. 100 μL of a stain solution (0.05% crystal violet in a 20% methanol solution) was added to each well and allowed to stand for 30 minutes, then the plate was washed 10 times with water and was dried. 100 μL of an extract solution (0.1 N NaH₂PO₄: 100% ethanol=1:1) was added to each well and mixed, and the mixture was measured at a wavelength of 540 nm using a plate reader (MTP-450 manufactured by Corona Electric Co., Ltd.). The growth inhibition rate was calculated from the following formula, and the concentration (IC₅₀ (μM)) of a test compound inhibiting 50% was determined. The results are shown in Table 20. Growth inhibition rate (%)={(C−B)−(T−B)}/(C−B)×100

T: Absorbance of well to which test compound was added

C: Absorbance of wells to which no test compound was added

B: Absorbance of wells to which no cell suspension was added

As a result, as is clear from the following table, it was revealed that the compounds of the present invention have growth inhibitory activity against cancer cells.

TABLE 20 Cell growth Example suppression Number IC₅₀ (μM)  1 0.16  5 0.20  6 0.29  10 0.56  11 0.64  12 0.50  13 0.31  14 0.56  15 0.40  18 0.58  19 0.94  25 0.59  26 0.98  30 0.80  35 0.67  37 0.82  39 0.23  40 0.59  41 0.40  43 0.28  71 0.79  76 0.44  83 0.50  91 0.98  93 0.28  94 0.48  95 0.14  96 0.95 100 0.39 101 0.81 102 0.66 106 0.38 109 0.40 113 0.60 114 0.37 116 0.32 117 0.31 123 0.17 129 0.08 144 0.96 146 0.83 147 0.65 148 0.40 153 0.91 156 0.87 157 0.37 167 0.14 186 0.64 193 0.11 196 0.32 197 0.41 198 0.05 200A 0.05 200B 0.46 203 0.81 204 0.15 205 0.25 206A 0.57 207A 0.07 207B 0.25 208A 0.33 208B 0.05 209A 0.06 209B 0.82 211A 0.85 212 0.26 216 0.67 220A 0.37 220B 0.50 222A 0.06 222B 0.67 224A 0.10 224B 0.77 225A 0.60 226A 0.08 226B 0.30 227A 0.19 228A 0.14 229A 0.31 230A 0.29 230B 0.78 232 0.33 233 0.28 234A 0.57 235A 0.13 235B 0.40 238A 0.44 239A 0.72 241 0.49 243A 0.29 243B 0.70 244A 0.72 245 0.15 249 0.14 250 0.12 252 0.74 253 0.23 254 0.25 255 0.48 257 0.20 258 0.58 259 0.35 261 0.72 262 0.17 264 0.76 273 0.81 275 0.37 278 0.59 288 0.15 289 0.60 292 0.75 294 0.39 303 0.99 304 0.94 308 0.87 310 0.35 311 0.52 312 0.87 315 0.93 328 0.41 329 0.24 330A 0.24 337 0.30

Test Example 3 Cell Proliferation Inhibitory Effect on Human Cancer-Derived Cancer Cell Lines

According to the method of Test Example 2, the cell proliferation inhibitory effect on various cancer cell lines as described in Table 21 was evaluated.

As a result, as is clear from the following table, it was revealed that the compounds of the present invention have growth inhibitory activity against various types of cancer cells derived from humans.

TABLE 21 cell line NUGC-3 NCI-H460 CFPAC-1 A673 GB-1 HLE MSTO-211H DU145 Carcinoma Stomach Lung Cancer Pancreatic Ewing's Glioblastoma Liver Mesothelioma Prostate Cancer type Cancer Cancer sarcoma Cancer Culture RPMI- ATCC IMDM + DMEM + DMEM + DMEM + ATCC EMEM + medium 1640 + recommended 10% FBS 10% 10% FBS 10% FBS recommended 0.1 mM non-essential 10% RPMI-1640 + FBS RPMI-1640 + amino acid + FBS 10% FBS 10% FBS 1 mM sodium pyruvate + 10% FBS cell number 2000 1000 2000 2000 3000 3000 6000 5000 (cell/well) Example 5 1.22 0.73 0.94 1.09 1.57 0.79 0.70 1.04 Example 235A 0.71 0.35 0.35 0.61 1.12 0.42 0.39 0.53 Example 11 3.11 1.50 1.71 2.56 5.22 1.74 1.54 1.84 Example 1 1.12 0.57 0.54 0.92 1.56 0.56 0.65 0.73 Example 14 2.83 1.35 1.42 1.85 4.60 1.30 1.58 2.22 Example 209A 0.40 0.25 0.33 0.32 0.64 0.26 0.32 0.31 Example 222A 0.36 0.18 0.23 0.25 0.46 0.20 0.27 0.26 Example 200A 0.27 0.13 0.17 0.18 0.37 0.14 0.17 0.17 Example 228A 0.51 0.31 0.36 0.40 0.85 0.29 0.37 0.34 cell line A2780 ACHN HCT116 RPMI7932 NCI-H2228 NCI-H2170 Carcinoma type Ovarian Cancer Kidney Cancer Colorectal Cancer Melanoma Lung Cancer Lung Cancer Culture medium RPMI-1640 + EMEM + McCoy's 5A + RPMI-1640 + ATCC ATCC 10% FBS 10% FBS 10% FBS 10% FBS recommended recommended RPMI-1640 + RPMI-1640 + 10% FBS 10% FBS cell number 2000 2000 1000 4000 5000 5000 (cell/well) Example 5 0.83 0.75 0.91 2.67 1.27 1.89 Example 235A 0.40 0.38 0.48 1.23 0.88 1.10 Example 11 2.08 1.50 2.30 4.74 3.21 3.90 Example 1 0.63 0.68 0.75 1.74 1.35 1.41 Example 14 1.71 0.98 2.20 3.21 3.53 4.18 Example 209A 0.30 0.22 0.28 0.72 0.73 0.57 Example 222A 0.19 0.17 0.27 0.51 0.48 0.52 Example 200A 0.13 0.13 0.22 0.43 0.50 0.49 Example 228A 0.38 0.32 0.38 0.65 0.74 0.88

Test Example 4 Evaluation of Antitumor Effect Using Human-Derived Blood Cancer Cell Line (MV-4-11) Subcutaneous Transplantation Model (In Vivo)

A human-derived blood cancer cell line MV-4-11 was transplanted subcutaneously into a nude mouse, and at the time when the tumor volume of the nude mouse on which the engrafted tumor reached about 100 to 300 mm³, five mice were assigned to each group by random stratification so that the average of the tumor volumes of each group was uniform (day 0), and the compound of the present invention was orally administered daily at 100 mg/kg/day once per day for 14 days. Mouse were killed during the experiments when they lost more than 20% weight based on ethical guidelines, and the final results are calculated based on each group consisting of four mice.

In order to compare the chronological transition of proliferation of tumor for the administration of each test compound, relative tumor volume (RTV) setting the tumor volume at the time of grouping as 1 as the tumor proliferation rate was calculated according to the following formula, and the transition of the average value of RTV of each individual are shown in FIGS. 1 to 4. RTV=(tumor volume at the day of tumor volume measurement)/(tumor volume at the time of the grouping)

The average RTV value of the compound-administered group of the present invention on the final evaluation day is smaller than the average RTV value of the control group, and when a statistically significant difference (Student-t test) is shown, the compound of the present invention was determined to be significantly effective, and the statically significant difference is marked with * in the figure (*: p<0.05).

As a result, it was revealed that the compound of the present invention shows a significant antitumor effect. 

The invention claimed is:
 1. A compound represented by the following formula (I):

wherein X¹ represents an oxygen atom or a sulfur atom; X² and X³ represent oxygen atoms; X² represents an oxygen atom, and X³ represents —NH—; or X² represents —NH—, and X³ represents an oxygen atom; X⁴ represents a hydrogen atom or a C1-C6 alkyl group; R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—; R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, or a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms; R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group, wherein R² may have substituents, and when R² has two substituents on carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents, R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group, wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and R⁴ represents a hydrogen atom or a C1-C6 alkyl group; with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom, or a salt thereof.
 2. The compound or a salt thereof according to claim 1, wherein in formula (I): R¹¹ represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group; R¹² represents a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group; or R¹¹ and R¹² may be taken together with carbon atoms to which R¹¹ and R¹² bind to form a saturated hydrocarbon ring having 3 to 8 carbon atoms.
 3. The compound or a salt thereof according to claim 1, wherein in formula (I), X¹ represents an oxygen atom.
 4. The compound or a salt thereof according to claim 1, wherein in formula (I), X² represents an oxygen atom.
 5. The compound or a salt thereof according to claim 1, wherein in formula (I), X³ represents —NH—.
 6. The compound or a salt thereof according to claim 1, wherein in formula (I), X⁴ represents a hydrogen atom.
 7. The compound or a salt thereof according to claim 1, wherein in formula (I), R¹ represents —C(R¹¹)(R¹²), wherein R¹¹ represents a C1-C6 alkyl group, and R¹² represents a hydrogen atom.
 8. The compound or a salt thereof according to claim 1, wherein in formula (I): R² represents a C6-C14 aromatic hydrocarbon group or a 9-10 membered fully unsaturated heterocyclic group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may be substituted with Rz; R²¹ represents: a halogen atom; an amino carbonyl group; a cyano group; a C1-C6 alkyl group optionally substituted with Rx; a C3-C6 cycloalkyl group optionally substituted with Rx; a C2-C6 alkynyl group optionally substituted with Rx; a C6-C14 aromatic hydrocarbon group optionally substituted with Ry; or a 5-10 membered unsaturated heterocyclic group optionally substituted with Rz; Rx represents a halogen atom or a C6-C14 aromatic hydrocarbon group; Ry represents a halogen atom or a C1-C6 alkoxy group; Rz represents a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, or a nitrogen-containing saturated heterocyclic carbonyl group.
 9. The compound or a salt thereof according to claim 1, wherein in formula (I): R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group, wherein R³ may be substituted with R³¹, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituent may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may be substituted with Rc; R³¹ represents: a halogen atom; a cyano group; a nitro group; a carboxyl group; a thioamide group; a C1-C6 alkyl group optionally substituted with Ra; an amino group optionally substituted with Ra; a C3-C6 cycloalkyl group optionally substituted with Rb; a C1-C6 alkoxy group optionally substituted with Rb; a C2-C7 alkoxycarbonyl group; a C1-C14 acyl group optionally substituted with Rb; a C6-C14 aromatic hydrocarbon group optionally substituted with Rb; a 5-10 membered unsaturated heterocyclic group optionally substituted with Rc; an amino carbonyl group optionally substituted with Rd and Re; or —S(═O)₂Rf; Ra represents a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group; Rb represents a halogen atom, an amino group, or a C1-C6 alkoxy group; Rc represents: a halogen atom; a hydroxy group; an amino group; an oxo group; a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl groups; a C1-C14 acyl groups; a C1-C14 acylamino group; a C1-C14 acyloxy group; or a C7-C13 aralkyloxy group; Rd and Re are the same or different and represents: a hydrogen atom; a hydroxy group; a C7-C13 aralkyloxy group; or a C1-C6 alkyl group optionally substituted with a hydroxy group; alternatively combine with nitrogen atom which is adjacent to Rd and Re to form a saturated or unsaturated 4-10 membered heterocyclic ring group optionally substituted with an amino group, a spiro heterocyclic ring group, or a bridged heterocyclic ring group; and Rf represents an amino group, a C1-C6 alkyl group, or a 4-10 membered saturated heterocyclic group.
 10. The compound or a salt thereof according to claim 1, wherein in formula (I): R² represents a C6-C14 aromatic hydrocarbon group or a bicyclic 9-10 membered fully unsaturated heterocyclic ring group having 1-3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 4-8 carbon atoms optionally substituted with a C1-C6 alkyl group, or a saturated or partially unsaturated monocyclic 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a C1-C6 alkyl group; R²¹ represents a halogen atom, an amino carbonyl group, a cyano group, a C1-C6 alkyl group optionally substituted with a halogen atom, a C3-C6 cycloalkyl group, a C2-C6 alkynyl group optionally substituted with a C6-C14 aromatic hydrocarbons group, a C6-C14 aromatic hydrocarbon group optionally substituted with a group selected from a halogen atom and a C1-C6 alkoxy group, or an unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1-3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, and nitrogen-containing saturated heterocyclic carbonyl group.
 11. The compound or a salt thereof according to claim 1, wherein in formula (I): R² represents a C6-C14 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 4-8 carbon atoms optionally substituted with a C1-C6 alkyl group; R²¹ represents a halogen atom, a cyano group, a C1-C6 alkyl group optionally substituted with a halogen atom, a C3-C6 cycloalkyl group, a phenyl group optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkoxy group, or an unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1-3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group.
 12. The compound or a salt thereof according to claim 1, wherein in formula (I): R² represents a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 5 or 6 carbon atoms optionally substituted with a C1-C6 alkyl group; R²¹ represents a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6 membered unsaturated heterocyclic group having 1-3 nitrogen atom(s) optionally substituted with a C1-C6 alkyl group.
 13. The compound or a salt thereof according to claim 1, wherein in formula (I): R³ represents a C6-C14 aromatic hydrocarbon group, or a monocyclic or bicyclic 5-10 membered fully unsaturated heterocyclic group having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ may be substituted with R³¹, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 4-8 carbon atoms optionally substituted with a group selected from the group consisting of: a halogen atom; a hydroxyl group; an amino group; an oxo group; a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; a C1-C14 acyloxyl group; and a C7-C13 aralkyloxy group, or a saturated or partially unsaturated monocyclic 4-8 membered heterocyclic ring having 1-4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; a C1-C14 acyloxy group and a C7-C13 aralkyloxy group; R³¹ represents a halogen atom, a cyano group, a nitro group, a carboxyl group, thioamide group, C1-C6 alkyl group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, C1-C14 acyloxy group, C2-C6 alkynyl group, and C1-C6 alkoxy C1-C6 alkoxy group, an amino group optionally substituted with a C1-C14 acyl group, a C3-C6 cycloalkyl group optionally substituted with an amino group, a C1-C6 alkoxy group optionally substituted with a halogen atom, a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group optionally substituted with a halogen atom, a C6-C14 aromatic hydrocarbon group optionally substituted with a group selected from the group consisting of a halogen atom, an amino group and a C1-C6 alkoxy group, a monocyclic or bicyclic 5-10 membered unsaturated heterocyclic group having 1-4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a halogen atom, an oxo group and a C1-C6 alkyl group, an amino carbonyl group optionally substituted with Rd and Re wherein Rd and Re are the same or different, and present a hydrogen atom, a hydroxy group, a C7-C13 aralkyloxy group, or a C1-C6 alkyl group optionally substituted with a hydroxy group, alternatively combine with the adjacent nitrogen atom to form: a saturated or unsaturated monocyclic or bicyclic 4-10 membered heterocyclic group, optionally substituted with an amino group, having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom; a spiroheterocyclic group; or a bridged heterocyclic group, or —S(═O)₂Rf, wherein Rf represents an amino group, a C1-C6 alkyl group, or a 4-10 membered saturated heterocyclic group.
 14. The compound or a salt thereof according to claim 1, wherein in formula (I): R³ represents a C6-C10 aromatic hydrocarbon group or a monocyclic or bicyclic 5-10 membered fully unsaturated heterocyclic group having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ may be substituted with R³¹, when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, R³ may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated monocyclic hydrocarbon having 4-8 carbon atoms optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, C1-C6 alkyl groups (which are optionally substituted with a hydroxy group), a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group, or a saturated or partially unsaturated monocyclic 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a halogen atom; a hydroxy group; an amino group; an oxo group; and a C1-C6 alkyl group which is optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; a C1-C14 acyloxy group; R³¹ represents a halogen atom, a cyano group, a nitro group, a carboxyl group, thioamide group, C1-C6 alkyl group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, and a C1-C6 alkoxy C1-C6 alkoxy group, an amino group optionally substituted with a C1-C14 acyl group, a C3-C6 cycloalkyl group optionally substituted with an amino group, a C1-C6 alkoxy group optionally substituted with a halogen atom, a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group optionally substituted with a halogen atom, a C6-C10 aromatic hydrocarbon group optionally substituted with a group selected from the group consisting of an amino group and a halogen atom, an unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a C1-C6 alkyl group and an oxo group, a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyamino carbonyl group, (C7-C13 aralkyl)oxyaminocarbonyl group, a cyclic aminocarbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl group.
 15. The compound or a salt thereof as in claim 1, wherein in formula (I): R³ represents a C6-C10 aromatic hydrocarbon group wherein the C6-C10 aromatic hydrocarbon group may be substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated monocyclic 4-6 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acyl amino group and a C1-C14 acyloxy group, alternatively presents a fully unsaturated monocyclic 5 or 6 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxy group, a C1-C6 alkoxy group, a C2-C7 alkoxycarbonyl group, a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group, a 3-oxa-8-azabicyclo[3.2.1]octanyl group and an 8-oxa-3-azabicyclo[3.2.1]octanyl group, R³¹ represents a halogen atom, an amino group, a C1-C6 alkyl group optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group, C1-C6 alkoxy group optionally substituted with a halogen atom, a monocyclic 5 or 6 membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono- or di-C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino carbonyl group.
 16. The compound or a salt thereof according to claim 1, wherein in formula (I): X¹ represents an oxygen atom, X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —C(R¹¹)(R¹²)— wherein R¹¹ represents a C1-C6 alkyl group, and R¹² represents a hydrogen atom, and R² represents a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituent may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 5 or 6 carbon atoms optionally substituted with a C1-C6 alkyl group; and R²¹ represents a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6 membered unsaturated heterocyclic group having 1-3 nitrogen atom(s) optionally substituted with a C1-C6 alkyl group; R³ represents a C6-C10 aromatic hydrocarbon group wherein the C6-C10 aromatic hydrocarbon group may be substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substitutes may be fused together with carbon atoms to which the substituents bind to form a saturated or partially unsaturated monocyclic 4-6 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group; a C1-C14 acyl amino group and a C1-C14 acyloxy group, alternatively presents a fully unsaturated monocyclic 5 or 6 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxy group, a C1-C6 alkoxy group, a C2-C7 alkoxycarbonyl group, a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group, a 3-oxa-8-azabicyclo[3.2.1]octanyl group and an 8-oxa-3-azabicyclo[3.2.1]octanyl group, R³¹ represents a halogen atom, an amino group, a C1-C6 alkyl group optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group, a C1-C6 alkoxy group optionally substituted with a halogen atom, a monocyclic 5 or 6 membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono- or di-C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino carbonyl group, R⁴ represents a hydrogen atom.
 17. The compound or a salt thereof according to claim 1, wherein in formula (I): X¹ represents an oxygen atom, X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —C(R¹¹)(R¹²)— wherein R¹¹ represents a methyl group, and R¹² represents a hydrogen atom, and R² represents a phenyl group, or a naphthyl group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents bind, to form a saturated or partially unsaturated monocyclic hydrocarbon ring having 5 or 6 carbon atoms optionally substituted with a C1-C6 alkyl group; and R²¹ represents a halogen atom or a C1-C6 alkyl group; R³ represents a phenyl group, wherein the phenyl group may be substituted with R³¹, and when a phenyl group has two substituents on the carbon atoms which are adjacent to each other on a benzene ring, the substitutes may be fused together with carbon atoms to which the substituents bind, to form a saturated or partially unsaturated monocyclic 6 membered heterocyclic ring having 1 or 2 oxygen atom(s) optionally substituted with a group selected from the group consisting of a hydroxy group and a C1-C6 alkyl group, or a pyridyl group optionally substituted with a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, or a pyrrolidin-1-ylcarbonyl group; R³¹ represents a halogen atom, an amino group, a C1-C6 alkyl group or a —CONH₂ group; R⁴ represent a hydrogen atom.
 18. The compound or a salt thereof according to claim 1, wherein the compound is selected from the following compounds (1)-(19): (1) 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (2) 5-chloro-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (3) 5-bromo-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (4) 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (5) 5-chloro-2-(N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (6) 5-chloro-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (7) 5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (8) 5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide, (9) 2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chloro-benzamide, (10) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(pyrrolidine-1-carbonyppyridine-2-sulfonamide, (11) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide, (12) 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-chroman-8-sulfonamide, (13) N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methyl-chroman-8-sulfonamide, (14) 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide, (15) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide, (16) 3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N,N-dimethylpicolinamide, (17) 4-amino-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide, (18) 4-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide, and (19) 5-chloro-2-[[(1S,2R)-3,3,3-trideuterio-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]sulfamoyl]benzamide. 